Laparoscopic Pelvic Autonomic Nerve-Preserving Surgery for Sigmoid Colon Cancer Background To test the feasibility of laparoscopic approach in performing the simultaneous pelvic autonomic nerve preservation during standard anterior resection of sigmoid colon cancer . Preservation of pelvic autonomic nerves to retain genitourinary function without compromise of oncologic clearance of tumor has been extensively studied in rectal cancer surgery .1 -- 12 However , there is still not much information on sexual and bladder function after the curative resection of sigmoid colon cancer . Theoretically , the pelvic autonomic nerve-preserving surgery is technically much easier during a sigmoid colon resection , as apposed to rectal surgery , because the pelvic deep-seated neural structures , such as pelvic plexus -LRB- inferior hypogastric plexus -RRB- , lateral ligament , neurovascular bundles of Walsh , and periprostate plexus , were not within the boundary of dissection .13 -- 17 It is therefore our opinion that during the anterior resection of sigmoid colon cancer , preservation of autonomic nerves is a priority -- that is , autonomic nerve preservation is appropriate unless there are oncologic reasons for the resection of nerves , e.g. , the nerves were directly involved by cancer , in terms of better postoperative genitourinary function for the patients . Recently , more and more sigmoid colon cancers were resected laparoscopically .18 -- 20 Therefore , we conducted the present study to test the feasibility of laparoscopic approach in performing the total pelvic autonomic nerve preservation during the standard oncologic resection of sigmoid colon cancer . We hypothesized that given a well-illuminated magnified view by laparoscopy , the autonomic nerves can be well protected from inadvertent surgical damage . PATIENTS AND METHODS Patients meeting the following eligibility criteria were recruited for the present study . The inclusion criteria were : -LRB- 1 -RRB- curative and elective surgery ; -LRB- 2 -RRB- sigmoid adenocarcinoma with tumor location generally 15 to 40 cm above anal verge ; -LRB- 3 -RRB- American Society of Anesthesiology function class I to class III patients ; -LRB- 4 -RRB- age between 18 to 65 years . The exclusion criteria were : -LRB- 1 -RRB- emergency or urgent surgery ; -LRB- 2 -RRB- evidence of tumor invasion to adjacent organs or distant metastasis ; -LRB- 3 -RRB- previous major abdominal or pelvic surgery ; -LRB- 4 -RRB- abnormal preoperative baseline genitourinary function on the basis of validated questionnaire-based interview .10,21,22 Before entering the present study , all patients were well explained regarding the surgical procedures , and informed consents were obtained . The present study was approved by the Institutional Review board of National Taiwan University Hospital and was designated as NTUH 93S-024 . Surgical Strategy The related neuroanatomy for the nerve-preserving surgery of sigmoid colon cancer is shown in Fig. 1A . The preservation of autonomic nerves was focused on the following three anatomic sites : -LRB- 1 -RRB- inferior mesenteric plexus -LRB- Fig. 1B -RRB- ; -LRB- 2 -RRB- superior hypogastric plexus -LRB- Fig. 1C -RRB- ; and -LRB- 3 -RRB- the paired hypogastric nerves -LRB- Fig. 1D -RRB- . The details of surgical procedures were well recorded and are shown in the associated video . Fig. 1 -LRB- A -RRB- Surgical anatomy of pelvic anatomic nerves related to the nerve-preserving surgery of sigmoid colon cancer . -LRB- B -RRB- The inferior mesenteric plexus -LRB- yellow arrow -RRB- encircles the root of inferior mesenteric artery -LRB- IMA -RRB- . -LRB- C -RRB- The superior hypogastric plexus overlying the interiliac trigone area . -LRB- D -RRB- The right hypogastric nerve travels across the presacral areolar tissue and then adheres to the proper rectal fascia . To ensure the visualization and preservation of the nerves at all three critical points , we used a specific point-by-point checklist during the operations . The dissection commences at the medial side of sigmoid mesentery at the level of pelvic promontory . By gentle tenting of the sigmoid mesocolon ventrally , the superior hypogastric plexus was identified and preserved at the interiliac trigone just below the peritoneum . Subsequently , the dissection was continued upward along the ventral side of abdominal aorta . The preaortic plexus were then preserved by sparing the preaortic connective tissue . Thereafter , the medial-to-lateral laparoscopic dissection along the areolar tissue between sigmoid mesocolon and Gerota fascia was performed . The medial approach is well adapted for laparoscopy because it provides the working space and demands the least handling of sigmoid colon .23 During the mobilization of sigmoid mesocolon , we did not identify the ureter because the loose connective tissue between Gerota fascia and sigmoid mesocolon is a natural dissection plane . Normally , the ureter and gonadal vessels are covered by the Gerota fascia , and therefore , if the ureter is clearly or intentionally identified , it means that the Gerota fascia is opened and the dissection plane may be imprecise . By simultaneous upward and medial-to-lateral dissection , we subsequently reach the junction of inferior mesenteric artery -LRB- IMA -RRB- and abdominal aorta . The IMA was divided 1 to 2 cm distal to its origin , or just distal to the left colic branch . This is because the sympathetic fibers encircle the IMA at the level of IMA 's origin from abdominal aorta . If the nerves are not adequately cleared from `` behind '' the IMA , they can be easily damaged at this point -LRB- Fig. 1B -RRB- . Subsequently , the `` holy plane '' at the transition of the mesosigmoid to the mesorectum was meticulously dissected to progressively displace the hypogastric nerves dorsally and laterally -LRB- Fig. 1D -RRB- , and thus preserve them . Assessment of Urinary Function Urinary function was evaluated on the basis of questionnaire-based interview of patients preoperatively and 3 months after surgery . In patients with major surgical complications , for example , anastomotic leakage , the urinary function was evaluated 3 months after recovery from surgical morbidity , i.e. , 3 months after the closure of defunctioning ileostoma . The preoperative functional questionnaire was based on the recollection of function before the development of symptoms from sigmoid colon cancer . Routinely , the urine Foley catheter was inserted for the patients immediately before the operation . In the postoperative period , the date for urine removal of the Foley catheter and the nature of any voiding problems , such as those requiring recatheterization , were recorded . The duration of indwelling urine Foley catheter was counted from the time of insertion to the time of its removal . The questionnaire used was based on International Prostate Symptom Score -LRB- IPSS -RRB- , the parameters of which included incomplete bladder emptying , frequency , intermittency , urgency , weak stream , straining , and nocturia . Further subdivisions were added to the seven items .10 The scoring system for voiding function described above was based on a 0 to 5 scale , as follows : 0 , not at all ; 1 , less than one time in five ; 2 , less than half the time ; 3 , approximately half the time ; 4 , more than half the time ; 5 , almost always . IPSS was calculated by adding the item scores . We ranked the urinary function as good -LRB- IPSS , 0 -- 7 -RRB- ; fair -LRB- IPSS , 8 -- 14 -RRB- , and poor -LRB- IPSS , 15 -- 35 -RRB- . Any voiding problems recovered within 3 months after surgery was considered to be transient bladder voiding dysfunction ; otherwise , the voiding problems were deemed persistent . Assessment of Sexual Function Sexual function was evaluated preoperatively and 6 months after operation or recovery from surgical complications , if present . In male patients , the sexual function was evaluated on the basis of potency and ejaculation . The ejaculatory function was graded as good , fair -LRB- decrease in ejaculatory amounts up to 50 % -RRB- , and poor -LRB- retrograde ejaculation , failure to ejaculate -RRB- . The grade of potency disorder was measured on the basis of the International Index of Erectile Function -LRB- IIEF -RRB- , which contains five index domains -LRB- erectile function , orgasm function , sexual desire , intercourse satisfaction , and overall satisfaction -RRB- and 15 items .21 Each item of the IIEF is scored on a 5 - or 6-point Likert score . Score for each domain are variable , and the total score range is 5 to 75 . We classified the male potency function as good -LRB- IIEF , 60 -- 75 -RRB- , fair -LRB- IIEF , 44 -- 59 -RRB- , and poor -LRB- IIEF , 5 -- 43 -RRB- . In female patients , sexual function was evaluated on the basis of the Female Sexual Function Index -LRB- FSFI -RRB- , which is a 19-item validated questionnaire that was designed to evaluate female sexual dysfunction , especially female sexual arousal disorder .22 The scale is divided into six domains : desire , arousal , lubrication , orgasm , satisfaction , and pain . Each item is scored with a 5 - or 6 - point Likert scale . The scales for each domain are variable , and the total score range is 4 to 95 . For the present study , we classified the female sexual function as good -LRB- FSFI , 76 -- 95 -RRB- , fair -LRB- FSFI , 58 -- 75 -RRB- , and poor -LRB- FSFI , 4 -- 57 -RRB- . Furthermore , the specific sexual problems in women such as libido , arousal , lubrication , orgasm , and dyspareunia were investigated . Data Management Data on patients undergoing laparoscopic autonomic nerve-preserving surgery for sigmoid colon cancer between January 2004 and December 2006 were entered into a prospective database of the present study . Until June 2007 , the mean time of follow-up for the patients was 18 months , ranging from 6 to 36 months . The genitourinary function of the patients was analyzed by the intention-to-treat principle . Patients were first contacted by telephone by a research assistant who described the nature of the project . Those who consented to the present study were given a questionnaire-based interview by the research assistant . The data were managed by a statistician . To prevent bias of evaluation , the research assistant was not told which surgical procedure was performed for each individual patient . Because genitourinary function is influenced by preoperative function and numerous other variables , including the emotional and physiological status of the patients , as well as other influences such as chemotherapy , each patient was used as his or her own control in evaluating the change of function before and after surgery . The two sets of measurements on the same patient were compared , and the P value was calculated from paired t-tests . A statistically significant level of difference was set at a P value of ≤ .05 . RESULTS A total of 112 patients were operated on with the intent of total preservation of pelvic autonomic nerves and curative resection of sigmoid colon cancer . The demographics and clinicopathologic data are shown in Table 1 . The nerve-preserving surgery was considered as failed in four patients when the videos of the surgical procedures were rescrutinized by coauthor colorectal surgeons and one general surgeon . The nerve-preserving anterior resection of sigmoid colon was performed with acceptable operation time , little blood loss , and low morbidity . The number of dissected lymph node was adequate , and the short-term oncologic result was good . Table 1Demographics , clinicopathologic data , and surgical outcomes of patients undergoing laparoscopic autonomic nerve-preserving surgery for sigmoid colon cancer -LRB- n = 112 -RRB- ParameterValueaAge -LRB- years -RRB- 55.8 ± 6.4 Sex -LRB- M/F -RRB- 58/54Body mass index -LRB- weight/height2 , kg/m2 -RRB- , mean -LRB- range -RRB- Male23 .4 -LRB- 20.3 ∼ 31.6 -RRB- Female24 .8 -LRB- 22.0 ∼ 32.5 -RRB- ASA class I62 II46 III4TME stage -LRB- pathologic -RRB- I8 II54 III50Operative time -LRB- minutes -RRB- 184.4 ± 44.8 Conversion rate .9 % -LRB- n = 1 -RRB- Blood loss -LRB- mL -RRB- 84.5 ± 24.0 Postoperative ileus -LRB- hours -RRB- 48.0 ± 8.4 Hospitalization -LRB- days -RRB- 8.0 ± 2.0 Postoperative pain -LRB- visual analog scale -RRB- 3.5 ± .4 Postoperative complication Total7 .1 % -LRB- n = 8 -RRB- Wound infection4 Deep vein thrombosis1 Pneumonia 1 Anastomotic leakage2No . of lymph nodes collected14 .4 ± 4.0 Tumor recurrence rate8 .0 % -LRB- n = 9 -RRB- ASA , American Society of Anesthesiology ; TNM , tumor , node , metastasis system.a Continuous data are presented as mean ± SD . In patients with successful nerve-preserving surgery -LRB- 96.4 % , n = 108 -RRB- , 104 patients completed the evaluation of urinary function -LRB- Table 2 -RRB- . The median duration of the indwelling urine Foley catheter was 3.0 days , ranging from 1.0 to 7.0 days . Preoperatively , the baseline urinary function of all patients was ranked as good -LRB- IPSS , 0 -- 7 -RRB- . However , after postoperative removal of the urine Foley catheter , the ranks of IPSS were changed to good in 98 patients -LRB- 94.2 % -RRB- , fair -LRB- IPSS , 8 -- 14 -RRB- in 5 -LRB- 4.8 % -RRB- , and poor -LRB- IPSS , 15 -- 35 -RRB- in 1 -LRB- 1.0 % -RRB- . There was no significant difference of preoperative and postoperative IPSS score -LRB- P = .075 , paired t-test -RRB- in patients with successful nerve-preserving surgery . The six patients with fair or poor bladder function experienced only transient dysfunction and recovered thereafter . Forty-four male and 42 female patients who were sexually active before the operation , i.e. , whose ejaculatory function , IIEF , and FSFI score were all ranked as good , responded to the assessment of sexual function . Postoperatively , in male patients -LRB- Table 3 -RRB- , the ranks of ejaculatory function were changed to good in 40 -LRB- 90.9 % -RRB- , fair -LRB- decrease in ejaculatory amounts -RRB- in 3 -LRB- 6.8 % -RRB- , and poor -LRB- retrograde ejaculation , failure of ejaculation -RRB- in 1 -LRB- 2.3 % -RRB- . The grades of the potency were changed to good -LRB- IIEF , 60 -- 75 -RRB- in 41 -LRB- 93.2 % -RRB- , fair -LRB- IIEF , 44 -- 59 -RRB- in 2 -LRB- 4.5 % -RRB- , and poor -LRB- IIEF , 5 -- 43 -RRB- in 1 -LRB- 2.3 % -RRB- . There was no significant difference of preoperative and postoperative IIEF score -LRB- P = .082 , paired t-test -RRB- in male patients whose pelvic autonomic nerves were successfully preserved during surgery . In female patients -LRB- Table 3 -RRB- , the ranks of sexual function were changed to good -LRB- FSFI score , 76 -- 95 -RRB- in 36 -LRB- 85.7 % -RRB- , fair -LRB- FSFI score , 58 -- 75 -RRB- in 4 -LRB- 9.5 % -RRB- , and poor -LRB- FSFI score , 4 -- 57 -RRB- in 2 -LRB- 4.8 % -RRB- . However , there was no significant change of FSFI score -LRB- P = .122 , paired t-test -RRB- for female patients before and after successful nerve-preserving surgery . Remarkably , specific sexual problems in women with autonomic nerve preservation included vaginal lubrication in 14.3 % -LRB- n = 6 -RRB- , dyspareunia in 9.5 % -LRB- n = 4 -RRB- , sexual arousal in 4.7 % -LRB- n = 2 -RRB- , and orgasm in 4.7 % -LRB- n = 2 -RRB- . Table 2Changes in urinary function before and after surgery for patients with successful nerve-preserving surgery -LRB- n = 104 -RRB- Urinary function -LRB- range of IPSS -RRB- Before operationAfter operationP valuea Good -LRB- 0 -- 7 -RRB- 10498 Fair -LRB- 8 -- 14 -RRB- 05 Poor -LRB- 15 -- 35 -RRB- 01IPSS score -LRB- mean ± SD -RRB- 3.20 ± 1.723.68 ± 2.82.075 IPSS , International Prostate Symptom Score.aP value was calculated on the basis of statistics of paired t-test . Table 3Changes in sexual function for male and female patients with successful nerve-preserving surgeryFunctionBefore OperationAfter OperationP valueaMale patients -LRB- n = 44 -RRB- Ejaculatory function Good4440 Fair03 Poor01Erectile function -LRB- IIEF Score -RRB- Good -LRB- 60 -- 75 -RRB- 4441 Fair -LRB- 44 -- 59 -RRB- 02 Poor -LRB- 5 -- 43 -RRB- 01IIEF score -LRB- mean ± SD -RRB- 72.4 ± 4.670.3 ± 8.4.082 Female patients -LRB- n = 42 -RRB- Sexual function -LRB- FSFI Score -RRB- Good -LRB- 76 -- 95 -RRB- 4236 Fair -LRB- 58 -- 75 -RRB- 04 Poor -LRB- 4 -- 57 -RRB- 02FSFI score -LRB- mean ± SD -RRB- 89.0 ± 9.285.4 ± 16.4.122 IIEF , International Index of Erectile Function ; FSFI , Female Sexual Function Index.aP value was calculated on the basis of statistics of paired t-test . Of the four patients -LRB- 3.6 % -RRB- who failed the procedures of the nerve-preserving surgery , three were female and one was male -LRB- Table 4 -RRB- . In them , the mean duration of indwelling urine Foley catheter was 6 days -LRB- range , 4 -- 8 days -RRB- . Although the genitourinary function for the four patients was normal before surgery , the single male patient 's IPSS and IIEF rank declined to the level of `` fair '' and he experienced retrograde ejaculation after the operation . The IPSS rank of the three female patients changed to the `` fair '' level in two , but the other patient remained at a `` good '' level after operation . The sexual function was adversely affected by the failure of nerve-preserving surgery , with a `` fair '' rank of FSFI in one patient and a `` poor '' rank in the remaining two patients . All three female patients experienced specific sexual problems , including vaginal lubrication , dyspareunia , sexual arousal , and orgasm . Table 4Changes of values in specific domains of the scoring system for evaluation of genitourinary function in patients who failed the procedures of nerve-preserving surgery -LRB- n = 4 -RRB- DomainPatient 1 -LRB- male -RRB- Patient 2 -LRB- female -RRB- Patient 3 -LRB- female -RRB- Patient 4 -LRB- female -RRB- Before OPAfter OPBefore OPAfter OPBefore OPAfter OPBefore OPAfter OPIPSS -LRB- score range -RRB- Total0100209012 1 . Incomplete emptying -LRB- 0 -- 5 -RRB- 02010404 2 . Frequency -LRB- 0 -- 5 -RRB- 02010102 3 . Intermittency -LRB- 0 -- 5 -RRB- 01000202 4 . Urgency -LRB- 0 -- 5 -RRB- 01000001 5 . Week stream -LRB- 0 -- 5 -RRB- 01000000 6 . Straining -LRB- 0 -- 5 -RRB- 02000203 7 . Nocturia -LRB- 0 -- 5 -RRB- 01000000IIEF -LRB- score range -RRB- Total7544 -- -- -- -- -- -- 1 . Erection function -LRB- 1 -- 30 -RRB- 3018 -- -- -- -- -- -- 2 . Orgasmic function -LRB- 0 -- 10 -RRB- 106 -- -- -- -- -- -- 3 . Sexual desire -LRB- 2 -- 10 -RRB- 106 -- -- -- -- -- -- 4 . Intercourse satisfaction -LRB- 0 -- 15 -RRB- 157 -- -- -- -- -- -- 5 . Overall satisfaction -LRB- 2 -- 10 -RRB- 107 -- -- -- -- -- -- FSFI Total -- -- 955895279532 1 . Desire -LRB- 2 -- 10 -RRB- -- -- 108104105 2 . Arousal -LRB- 0 -- 20 -RRB- -- -- 2012205206 3 . Lubrication -LRB- 0 -- 20 -RRB- -- -- 2010206206 4 . Orgasm -LRB- 0 -- 15 -RRB- -- -- 159153154 5 . Satisfaction -LRB- 2 -- 15 -RRB- -- -- 159153155 6 . Pain -LRB- 0 -- 15 -RRB- -- -- 1510156156IIEF , International Index of Erectile Function ; FSFI , Female Sexual Function Index . DISCUSSION The present study confirmed our hypothesis that by taking advantage of the optic properties of laparoscopy , we can precisely preserve the pelvic autonomic nerve at the following three anatomic sites : inferior mesenteric plexus , superior hypogastric plexus , and paired hypogastric nerves . However , we failed to preserve the autonomic nerve in four -LRB- one male and three female -RRB- patients of this case series -- a finding that needs to be addressed . After the completion of nerve-preserving surgery , we routinely tented the superior hypogastric plexus to check the total preservation of associated nerves . In our scrutiny of the surgical videos , we found that the mechanisms of nerve injury for the three female patients were the same : the nerve injuries were all located at the level of the hypogastric nerves and were bilateral . In our experience , the fibers of pelvic autonomic nerve were generally thinner in female that than in male patients . Furthermore , anatomically , the paired hypogastric nerves run downward , close to or tethering the proper rectal fascia along the pelvic wall -LRB- Fig. 1D -RRB- . At this point , the right-sided hypogastric nerves of the three female patients were subjected to avulsion injury . On the other hand , the left-side hypogastric nerves of these three female patients were mistaken as pelvic fibrotic bands and were cauterized . We thought that some female patients might be predisposed to chronic pelvic inflammation , thus blurring the pelvic dissection plane , and therefore the hypogastric nerves and retroperitoneal fibrotic bands could not be clearly differentiated , even under the well-illuminated and magnified view of laparoscopy . In the only male case of autonomic nerve injury , we found that the patient 's body mass index -LRB- BMI -RRB- was 32.0 kg/m2 . During the surgery , the hypogastric nerve was coated by fatty tissues and was inadvertently severed bilaterally . Because obese patients -LRB- BMI > 30 kg/m2 -RRB- represented only 6 -LRB- 10.3 % -RRB- of the 58 male and 4 -LRB- 7.4 % -RRB- of 54 female patients in this case series and nerve injury related to obesity occurred in only 1 male patient , we therefore were not sure whether high BMI was a risk factor for nerve injury . Further recruitment of more obese patients for study will be necessary to solve this interesting question . Remarkably , CaverMap Surgical Aid -LRB- CM ; Blue Torch Medical Technologies , Inc. , Ashland , MA -RRB- has been recommended to assist surgeons in intraoperatively localizing the autonomic nerves , ultimately leading to improved preservation of autonomic nerves and sexual function .24 We thought that CaveMap might be useful in case the nerve-preserving procedures were for the treatment of rectal cancer , in which case the neural structures to be preserved were deep-seated in the pelvis . However , for the oncologic resection of sigmoid colon cancer , the autonomic nerves at the above-mentioned three critical anatomic points were usually be clearly identified . In the rare cases when exact identification of the autonomic nerves was difficult , we recommended that the surgeons find the precise dissection plane between sigmoid mesentery and retroperitoneal tissue , and thus a plate of nerve-containing tissue overlying the abdominal aorta and interiliac trigone area can be left intact . On the other hand , the present study showed that laparoscopic nerve-preserving surgery for sigmoid colon cancer was technically feasible and could achieve function-preserving outcomes as good as those of traditional open surgery .10,11 However , the functional results of most reported series to date were based on the patients with rectal cancer undergoing open laparotomy . Therefore , further randomized studies in this respect that focus on sigmoid colon cancer are necessary . Neurophysiologically , the internal urethral orifice is innervated by sympathetic signals and has dual functions : one to ensure urinary continence , and the other to prevent backflow of semen during ejaculation . The present study provided the insights into the functional significance of the internal urethral orifice by the clinical observation that the female patients manifested some degree of urinary incontinence and the male patients experienced retrograde ejaculation as a result of the failed preservation of bilateral hypogastric nerves . However , the influence of damage of pelvic sympathetic nerves on female sexual function has been ambiguous but generally considered because it would most likely result in impairment of vaginal lubrication . The manifestation of specific sexual problems for the three female patients with inadvertent sympathectomy supported this hypothesis . Remarkably , our previous study on the canine modal showed that when one side of hypogastric nerve was severed , the other side of hypogastric nerve could compensate for the genitourinary functional loss to a normal level .15 To clarify the role of pelvic sympathetics in the human genitourinary function , further recruitment of more patients with iatrogenic sympathetic nerve injury for study is required . Because the intentional severance of sympathetic nerve during the surgical practice is not ethical , we think that further study subjects will be focused on patients with an advanced rectosigmoid cancer in which unilateral or bilateral sympathectomy was a necessity for the radical resection of cancer . In the present study , 6 patients -LRB- 5.8 % -RRB- had transient voiding disorder , 4 -LRB- 9.1 % -RRB- of 44 male patients had ejaculatory disorder , and up to 14.3 % -LRB- 6 of 42 -RRB- female patients had sexual problems after the operation , even though their sympathetic nerves were successfully preserved during surgery . Our explanations for this phenomenon were as follows : first , anatomically , the inferior mesenteric plexus , thoracolumbar sympathetic splanchnic nerves , and superior hypogastric plexus were grossly manifested as a continuous plate of weblike connective tissues underlying the root of IMA and overlying the lower abdominal aortic and the interiliac trigone area . Therefore , some minor partial injury of nerve fibers may not be detected during surgery . Second , the retroperitoneal dissection by electrocauterization sometimes causes side injury and/or ischemia change of nerve fibers and thus compromised the neurophysiologic function . Third , the sexual function is influenced by various psychosocial factors . For example , the alteration of body image and/or bowel function after the operation may also have negative effect on sexual function . Genitourinary functional disorders are generally subjective symptoms , and their measurement , either by questionnaire-based interviews or laboratory manometric and volumetric studies , are vulnerable to evaluation bias . Therefore , before the translation of technical feasibility of nerve-preserving surgery into the retaining of normal genitourinary function , the methodology used for the evaluation of functional outcomes in the present study needs to be further addressed . First , we used IPSS , IIEF , and FSFI to measure the genitourinary function of patients . These three kinds of validated questionnaires have been generally considered to be highly sensitive , and they have been widely adopted internationally for the study of genitourinary function .21,22 Second , in this study , both the patients and the assessors were informed of the intent to preserve the sympathetic nerves during sigmoidectomy but actually had no idea whether the nerve-preserving procedure was successful . The blinding of both assessors and patients to the surgical procedure can lessen the placebo effect . Third , the genitourinary function varies at different time points of evaluation . In this study , the evaluation of postoperative genitourinary function was conducted at the standardized time points before and after the operation . However , the preoperative baseline data was based on patient recall of genitourinary function before the appearance of bowel symptoms . The evaluation of baseline genitourinary function was therefore inevitably subject to methodology limitations , i.e. , the potential recall bias . However , to validate the preoperative baseline data of patients , the spouses or sexual partners of some selected patients were also interviewed . We emphasize that patients were included in this study only when their normal baseline genitourinary function was ensured . In conclusion , the genitourinary function of patients can be successfully preserved with good technical efficiency during laparoscopic sigmoidectomy . The present study should facilitate further study regarding the impact of preservation of genitourinary function on the postoperative quality of life for patients with sigmoid colon cancer . Electronic supplementary material Below is the link to the electronic supplementary material . -LRB- WMV 24856 kb -RRB-

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O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O

sigmoid colon cancer
pelvic autonomic nerve


Isolated

Hypoxic

Hepatic

Perfusion

with

Retrograde

Outflow

in

Patients

with

Irresectable

Liver

Metastases

A

New

Simplified

Technique

in

Isolated

Hepatic

Perfusion

Background

Isolated

hepatic

perfusion

with

high-dose

chemotherapy

is

a

treatment

option

for

patients

with

irresectable

metastases

confined

to

the

liver

Prolonged

local

control

and

impact

on

survival

have

been

claimed

Major

drawbacks

are

magnitude

and

costs

of

the

procedure

We

developed

an

isolated

hypoxic

hepatic

perfusion

-LRB-

IHHP

-RRB-

with

retrograde

outflow

without

the

need

for

a

heart-lung

machine

Approximately

of

colorectal

cancer

patients

will

develop

liver

metastases

during

follow-up

In

nearly

a

quarter

of

these

patients

the

liver

is

the

only

site

of

disease

If

hepatic

metastases

of

colorectal

cancer

are

resectable

survival

rates

are

reported

between

and

depending

on

several

prognostic

factors

Patients

with

irresectable

hepatic

metastases

have

a

survival

rate

and

a

median

survival

of

months

without

treatment

Therefore

aggressive

selective

treatment

of

the

liver

seems

justified

since

control

of

hepatic

metastases

translates

into

improved

overall

survival

Despite

the

increasing

response

rates

with

systemic

chemotherapeutic

agents

such

as

oxaliplatin

and

irinotecan

in

combination

with

and

the

promising

results

with

the

addition

of

angiogenesis

inhibitors

overall

survival

remains

poor

In

order

to

improve

responses

and

survival

locoregional

chemotherapeutic

regiments

have

been

developed

These

therapies

include

hepatic

arterial

embolization

intratumoral

injections

of

ethanol

acetic

acid

biological

agents

stereotactic

or

intra-arterial

radiotherapy

intralesional

laser

therapy

cryotherapy

radiofrequency

ablation

and

regional

infusion

or

perfusion

of

chemotherapeutic

drugs

The

best

approach

for

regional

infusion

of

chemotherapeutics

in

the

liver

is

unknown

Hepatic

artery

infusion

-LRB-

HAI

-RRB-

hepatic

artery

ligation

with

hepatic

artery

and

portal

vein

infusion

or

portal

vein

infusion

have

all

been

attempted

Of

these

modalities

HAI

is

the

most

widely

applied

form

A

number

of

studies

have

been

conducted

comparing

systemic

chemotherapy

with

HAI

and

a

modest

but

significant

improvement

of

survival

was

demonstrated

by

HAI

in

a

In

a

leakage-free

perfusion

setting

isolated

hepatic

perfusion

-LRB-

IHP

-RRB-

shields

the

systemic

compartment

to

drug

exposure

and

in

combination

with

a

washout

procedure

it

protects

against

systemic

toxicity

Clinical

studies

using

melphalan

with

or

without

tumor

necrosis

factor

alpha

-LRB-

TNF

-RRB-

have

shown

promising

results

However

IHP

is

a

major

complex

expensive

and

time-consuming

operation

These

features

in

combination

with

hepatic

and

systemic

toxicity

are

major

drawbacks

toward

wide

clinical

application

Our

aim

was

to

develop

an

IHP

that

is

easy

to

perform

with

limited

morbidity

or

mortality

not

time

consuming

and

with

minimal

costs

of

the

operation

without

affecting

the

antitumor

efficacy

We

started

an

isolated

hypoxic

hepatic

perfusion

-LRB-

IHHP

-RRB-

technique

with

percutaneously

placed

balloon

catheters

and

retrograde

outflow

without

a

heart-lung

machine

and

extracorporeal

venovenous

bypass

in

pigs

In

a

recent

study

we

demonstrated

the

feasibility

of

this

technique

-LRB-

retrograde

outflow

of

the

liver

-RRB-

in

a

clinical

setting

A

major

drawback

of

the

technique

was

systemic

leakage

rate

On

the

basis

of

these

results

we

modified

the

technique

by

applying

an

open

surgical

procedure

balloon

catheters

are

replaced

by

clamps

and

all

tributaries

to

the

vena

cava

such

as

the

adrenal

lumbar

and

diaphragmatic

veins

are

dissected

and

ligated

Here

we

present

the

results

of

the

first

patients

with

irresectable

liver

metastases

who

underwent

an

IHHP

with

melphalan

The

major

difference

between

this

new

technique

and

the

classic

IHP

is

that

there

is

no

veno-veno

bypass

and

heart-lung

machine

involved

and

the

drainage

of

the

liver

is

retrograde

through

the

portal

vein

MATERIALS

AND

METHODS

Patient

Selection

Criteria

Inclusion

criteria

were

as

described

previously

In

all

patients

a

radical

resection

of

the

primary

tumor

was

performed

prior

to

entering

the

study

protocol

except

for

one

patient

with

hepatic

metastasis

of

unknown

primary

The

liver

metastases

were

considered

irresectable

on

the

basis

of

multiple

lesions

in

multiple

segments

of

the

liver

and/or

location

near

vascular

structures

Tumor

involvement

had

to

be

less

than

of

the

total

liver

volume

to

prevent

massive

necrosis

in

case

of

a

response

Absence

of

extra

hepatic

tumor

growth

was

evaluated

by

computed

tomography

-LRB-

CT

-RRB-

scan

of

thorax

and

abdomen

All

patients

had

a

Karnofsky

performance

score

of

at

least

liver

enzymes

-LRB-

ALAT

ASAT

and

AF

-RRB-

not

higher

than

five

times

the

normal

values

and

bilirubin

not

higher

than

two

times

the

normal

values

Exclusion

criteria

included

age

younger

than

or

older

than

portal

hypertension

significant

central

nervous

system

disease

significant

cardiovascular

pulmonary

or

renal

disease

uncontrolled

infections

presence

of

organ

grafts

and

chemotherapy

or

radiation

therapy

within

weeks

prior

to

the

IHHP

Routinely

an

angiography

was

performed

to

exclude

aberrant

hepatic

arteries

or

to

visualize

other

anatomic

anomalies

The

study

protocol

was

approved

by

the

Medical

Ethical

Committee

of

the

Erasmus

University

Medical

Centre

and

written

informed

consent

was

obtained

from

all

patients

Perfusion

Circuit

Perfusion

sets

-LRB-

PfM

GmbH

Cologne

Germany

-RRB-

consisted

of

a

tubing

set

with

a

volume

of

mL

containing

a

bubble

trap

All

IHHPs

were

performed

with

inflow

via

the

hepatic

artery

and

outflow

via

portal

vein

In

the

perfusion

circuit

flow

was

maintained

by

a

roller

pump

and

pressure

was

measured

via

a

sideline

Drugs

A

dosage

of

mg/kg

melphalan

-LRB-

L-Pam

Alkeran

Wellcome

Ltd.

London

UK

-RRB-

was

used

in

of

the

patients

and

infused

through

a

sideline

into

the

perfusion

circuit

Two

times

mg/kg

melphalan

and

two

times

mg/kg

was

used

In

the

first

eight

patients

a

bolus

infusion

was

used

In

the

last

patients

a

pump

infusion

was

used

The

total

perfusion

-LRB-

infusion

included

-RRB-

with

melphalan

was

conducted

for

to

minutes

Surgical

Procedure

of

the

Retrograde

Flow

IHHP

A

right

subcostal

incision

was

performed

and

the

liver

was

mobilized

from

its

retroperitoneal

and

diaphragmatic

attachments

A

prophylactic

cholecystectomy

was

not

performed

routinely

Tributaries

to

the

vena

cava

such

as

the

adrenal

lumbar

and

diaphragmatic

veins

were

dissected

and

ligated

The

vena

cava

was

isolated

and

clamped

above

and

below

the

liver

respectively

to

prevent

venous

leakage

The

portal

vein

proper

hepatic

artery

and

gastroduodenal

artery

were

dissected

and

the

hepatic

artery

cannulated

via

the

gastroduodenal

artery

with

an

F

catheter

for

inflow

of

the

perfusate

In

two

patients

an

aberrant

left

hepatic

artery

coming

from

the

left

gastric

artery

was

cannulated

together

with

the

proper

hepatic

artery

for

inflow

The

portal

vein

was

cannulated

with

a

F

catheter

for

outflow

Patients

subsequently

received

mg/kg

heparin

The

hepatic

artery

catheter

and

the

portal

vein

catheter

were

connected

to

the

perfusion

circuit

primed

with

mL

Haemaccel

-LRB-

Behring

Pharma

Amsterdam

The

Netherlands

-RRB-

After

clamping

of

the

caval

vein

superior

and

inferior

of

the

liver

clamping

of

the

aorta

just

beneath

the

diaphragm

clamping

the

portal

vein

just

above

the

pancreas

clamping

the

proper

hepatic

artery

just

proximal

of

the

gastroduodenal

branch

and

clamping

of

the

common

bile

duct

with

its

surrounding

tissue

the

retrograde

isolated

perfusion

was

performed

The

retrograde

perfusion

setup

is

depicted

in

Fig.

FIG.

The

retrograde

perfusion

setup

The

perfusate

was

circulated

by

a

constant

flow

Stable

perfusion

was

monitored

by

pressure

measurement

and

the

perfusate

level

in

the

bubble

trap

Hereafter

melphalan

was

infused

into

the

circuit

and

the

perfusion

was

conducted

for

to

minutes

Thereafter

a

washout

procedure

was

performed

by

L

of

Haemaccel

collecting

the

venous

effluent

Total

liver

ischemia

time

never

exceeded

minutes

The

isolation

was

terminated

by

relief

of

the

clamps

on

the

caval

vein

followed

by

the

relief

of

the

aortic

clamp

controlling

systemic

blood

pressure

The

catheter

in

the

hepatic

artery

could

be

removed

and

the

gastroduodenal

artery

could

be

ligated

followed

by

decanulation

and

closing

the

venotomy

of

the

portal

vein

In

case

of

an

aberrant

left

hepatic

artery

this

artery

was

ligated

after

removal

of

the

catheter

Leakage

Monitoring

During

IHHP

potential

leakage

of

drugs

was

monitored

using

a

radioactive

tracer

A

small

calibration

dose

of

human

serum

albumin

radiolabeled

with

was

injected

into

the

systemic

circulation

prior

to

the

perfusion

and

higher

dose

of

the

same

isotope

was

injected

into

the

isolated

hepatic

perfusion

circuit

Continuous

monitoring

was

performed

with

a

precordial

scintillation

probe

Systemic

leakage

is

expressed

quantitatively

as

a

percentage

-LRB-

leakage

representing

a

homogeneous

distribution

of

the

isotope

in

the

body

-RRB-

Blood

Sampling

Before

during

and

after

the

perfusion

blood

samples

were

taken

and

collected

to

study

pharmacokinetics

of

melphalan

and

hematological

renal

hepatic

and

gastrointestinal

toxic

side

effects

Toxicity

is

graded

according

to

the

standardized

WHO

common

toxicity

criteria

Measurement

of

Melphalan

Concentrations

Melphalan

was

measured

in

plasma

by

gas

chromatography

mass

spectrometry

-LRB-

GC-MS

-RRB-

P

-LSB-

Bis

-LRB-

-RRB-

amino

-RSB-

phenylacetic

acid

methyl

ester

was

used

as

an

internal

standard

Samples

were

extracted

over

trifunctional

silica

columns

After

elution

with

methanol

and

evaporation

the

compounds

were

derivatized

with

trifluoroacetic

anhydride

and

diazomethane

in

ether

The

stable

derivates

were

separated

on

a

methyl

phenyl

siloxane

GC

capillary

column

and

measured

selectively

by

single

ion

monitoring

GC-MS

in

the

positive

EI

mode

described

earlier

by

Tjaden

et

al.

Assessment

of

Tumor

Response

This

was

done

by

comparing

pre-perfusion

CT

and/or

MRI

scans

of

the

liver

with

scans

made

at

weeks

after

IHHP

The

tumor

marker

carcinoembryonic

antigen

-LRB-

CEA

-RRB-

was

monitored

-LRB-

when

indicated

-RRB-

preoperatively

and

weeks

postperfusion

but

was

not

used

for

response

assessment

Clinical

responses

are

assessed

by

standardized

WHO

criteria

RESULTS

Patient

Characteristics

-LRB-

Table

-RRB-

In

a

total

of

consecutive

patients

males

and

females

with

a

median

age

of

years

-LRB-

range

-RRB-

were

included

in

the

protocol

Eighteen

patients

had

irresectable

metastases

of

colorectal

origin

four

ocular

melanomas

one

sarcomas

and

one

unknown

primary

hepatic

metastases

TABLE

Characteristics

of

patients

with

irresectable

liver

metastases

treated

by

IHHP

with

retrograde

outflow

via

portal

vein

with

melphalanPTTumor

primaryProgressive

on

chemotherapyToxicityResponse

after

perfusionTime

to

progr

-LRB-

months

-RRB-

StatusMonths

after

patient

number

CRC

colorectal

cancer

CR

complete

response

SARC

sarcoma

PR

partial

response

EM

eye

melanoma

SD

stable

disease

UP

unknown

primary

PD

progressive

disease

Operation

Characteristics

Median

operation

time

was

minutes

-LRB-

minutes

-RRB-

including

perfusion

time

Median

blood

and

fluid

loss

was

mL

-LRB-

mL

-RRB-

In

the

first

eight

patients

melphalan

was

administered

as

a

bolus

into

the

isolated

liver

circuit

The

last

patients

received

a

pump

infusion

of

melphalan

The

perfusion

-LRB-

infusion

included

-RRB-

with

melphalan

was

conducted

for

to

minutes

Perioperative

mortality

-LRB-

days

-RRB-

was

Median

hospital

stay

was

days

-LRB-

days

-RRB-

Leakage

Control

All

IHHPs

were

leakage

free

during

the

perfusion

except

in

one

patient

where

systemic

leakage

was

measured

When

this

perfusion

was

finished

it

appeared

that

in

this

patient

there

was

an

insufficient

clamping

of

the

suprahepatic

caval

vein

After

washout

of

the

isolated

circuit

with

Haemaccell

a

median

of

-LRB-

-RRB-

leakage

into

the

systemic

circuit

was

demonstrated

by

continued

monitoring

until

the

end

of

the

operation

Toxicity

Study

-LRB-

Table

-RRB-

Hepatic

toxicity

consisted

mainly

of

a

transient

rise

of

liver

enzymes

during

the

first

week

after

IHHP

WHO

grade

I

occurred

in

of

the

patients

-LRB-

of

-RRB-

and

WHO

grade

II

in

of

the

patients

-LRB-

of

-RRB-

Three

patients

experienced

bile

duct

necrosis

-LRB-

discussed

in

detail

in

the

section

Complications

-RRB-

No

other

hepatic

toxicities

occurred

-LRB-

no

coagulopathy

was

observed

-RRB-

Systemic

toxicity

was

mainly

leucopenia

WHO

grade

I

III

in

-LRB-

of

-RRB-

and

severe

grade

IV

leucopenia

in

one

patient

-LRB-

-RRB-

after

perfusion

Two

of

these

patients

received

G-CSF

-LRB-

Neupogen

Amgen

B.V.

Breda

The

Netherlands

-RRB-

One

patient

received

prophylactic

G-CSF

Eighteen

patients

-LRB-

-RRB-

did

not

develop

leucopenia

No

renal

-LRB-

except

for

one

patient

grade

-RRB-

or

gastrointestinal

toxicity

was

observed

Melphalan

Pharmacokinetics

Figure

shows

a

drug

concentration

vs

time

curve

in

the

isolated

circuit

in

a

patient

with

a

pump

infusion

The

area

under

the

concentration

versus

time

curve

-LRB-

AUC

-RRB-

calculation

showed

a

regional

concentration

of

-LRB-

μg

min/mL

-RRB-

versus

undetectable

systemic

that

makes

the

ratio

AUC

regional/systemic

infinite

-LRB-

Fig

II

-RRB-

The

median

peak

regional

melphalan

concentration

was

μg/mL

-LRB-

range

-RRB-

and

negligibly

low

to

undetectable

systemic

concentrations

After

washout

and

subsequent

releasing

of

the

clamps

median

peak

systemic

μg/mL

-LRB-

range

-RRB-

melphalan

concentrations

were

observed

The

AUC

calculation

showed

a

systemic

concentration

of

μg

min/mL

after

washout

Thus

intrahepatic

melphalan

concentrations

during

the

IHHP

are

fold

higher

than

the

post-IHHP

systemic

melphalan

concentrations

FIG.

versus

time

curve

Complications

In

three

patients

bile

duct

necrosis

occurred

-LRB-

Fig.

-RRB-

One

of

these

patients

was

asymptomatic

and

bile

duct

necrosis

was

found

on

routine

CT

scan

during

follow-up

Two

of

the

patients

with

bile

duct

necrosis

developed

fever

No

other

explanation

could

be

found

for

the

fever

besides

the

intrahepatic

bilomas

and

therefore

one

patient

was

treated

with

percutaneous

drainage

and

endoscopic

stent

placement

in

ductus

choledochus

The

other

patient

with

fever

received

antibiotics

Both

patients

recovered

and

slight

elevations

of

bilirubin

persisted

without

complaints

In

the

first

eight

patients

melphalan

was

administered

as

a

bolus

into

the

isolated

liver

circuit

After

four

patients

melphalan

dose

was

increased

to

mg/kg

in

two

patients

and

to

mg/kg

melphalan

in

another

two

patients

Three

of

these

patients

-LRB-

-RRB-

developed

bile

duct

necrosis

which

is

why

the

other

patients

were

treated

with

mg/kg

melphalan

using

a

pump

infusion

into

the

circuit

Bile

duct

necrosis

did

not

occur

in

these

patients

Postoperative

chemical

cholecystitis

was

not

demonstrated

FIG.

bile

duct

necrosis

after

IHHP

Tumor

Response

and

Patient

Survival

-LRB-

Table

-RRB-

In

one

patient

a

complete

response

was

observed

-LRB-

-RRB-

Partial

response

-LRB-

PR

-RRB-

was

seen

in

patients

-LRB-

-RRB-

and

stable

disease

-LRB-

SD

-RRB-

was

demonstrated

in

three

patients

-LRB-

-RRB-

Overall

a

clinical

response

rate

of

and

a

clinical

benefit

of

nonprogression

in

were

observed

Six

patients

developed

progressive

disease

-LRB-

-RRB-

Progressive

disease

occurred

with

median

interval

after

IHHP

of

months

-LRB-

range

months

-RRB-

Sixteen

patients

had

progression

of

the

liver

tumors

during

follow-up

Fourteen

patients

developed

extrahepatic

disease

during

follow-up

To

analyze

the

response

rates

and

survival

it

may

be

more

opportune

to

include

only

the

patients

with

colorectal

liver

metastases

Median

follow-up

was

months

Median

patient

survival

for

patients

with

colorectal

liver

metastases

-LRB-

n

-RRB-

was

months

-LRB-

range

months

-RRB-

Median

time

to

progression

was

months

-LRB-

months

-RRB-

Seven

of

these

patients

experienced

failures

of

systemic

chemotherapy

Two

patients

-LRB-

PtNo

and

-RRB-

were

progressive

on

the

combination

of

-LRB-

-RRB-

and

oxaliplatin

-LRB-

FOLFOX

-RRB-

-LRB-

and

cycles

respectively

-RRB-

two

patients

-LRB-

PtNo

and

-RRB-

were

progressive

on

and

leucovorine

-LRB-

and

cycles

respectively

-RRB-

one

patient

-LRB-

PtNo

-RRB-

was

progressive

after

Xeloda

-LRB-

four

cycles

-RRB-

and

irinotecan

-LRB-

four

cycles

-RRB-

one

patient

-LRB-

PtNo

-RRB-

after

six

cycles

of

FOLFOX

and

four

cycles

of

irinotecan

and

one

patient

-LRB-

PtNo

-RRB-

was

progressive

after

Xeloda

-LRB-

six

cycles

-RRB-

irinotecan

-LRB-

six

cycles

-RRB-

and

combination

of

Xeloda

and

oxaliplatin

-LRB-

XELOX

-RRB-

-LRB-

eight

cycles

-RRB-

Median

survival

for

patients

with

colorectal

liver

metastases

not

treated

with

chemotherapy

before

IHP

-LRB-

n

-RRB-

was

months

-LRB-

range

months

-RRB-

DISCUSSION

Isolated

liver

perfusions

are

only

performed

by

a

few

centers

worldwide

demonstrating

promising

antitumor

effects

however

the

technique

is

a

major

complex

expensive

and

time-consuming

operation

In

the

present

study

we

describe

an

alternative

technique

using

a

retrograde

hepatic

flow

in

an

isolated

hypoxic

hepatic

perfusion

-LRB-

IHHP

-RRB-

system

The

technique

was

performed

in

patients

and

demonstrated

to

be

safe

with

minimal

morbidity

and

no

morbidity

Overall

response

rate

was

with

no

progression

in

and

median

time

to

progression

of

disease

was

months

The

magnitude

of

the

standard

isolated

liver

perfusion

technique

is

well

demonstrated

in

two

recently

published

series

by

the

centers

with

the

largest

experience

in

IHP

-LRB-

NCI

Bethesda

MD

USA

and

LUMC

Leiden

The

Netherlands

respectively

-RRB-

Median

IHP

operation

time

was

reported

to

be

more

than

hours

-LRB-

range

hours

-RRB-

In

the

study

of

Bartlett

et

al.

the

estimated

blood

loss

was

L

-LRB-

range

L

-RRB-

and

Rothbarth

et

al.

reported

a

range

of

L

-LRB-

median

not

given

older

series

mean

of

L

-RRB-

Mortality

-LRB-

days

-RRB-

occurred

in

both

series

with

in

the

Leiden

series

-LRB-

n

-RRB-

and

in

the

NCI

series

-LRB-

n

-RRB-

Classical

IHP

uses

a

venovenous

bypass

and

a

heart-lung

machine

which

is

a

time-consuming

procedure

necessitating

a

specialized

perfusion

team

In

the

present

study

a

modification

was

developed

allowing

a

safe

perfusion

in

a

shorter

operation

time

-LRB-

median

duration

hour

-RRB-

with

less

blood

loss

-LRB-

median

cc

-RRB-

reducing

morbidity

and

without

mortality

without

the

need

of

a

heart-lung

machine

or

venovenous

bypass

The

absence

of

mortality

-LRB-

days

-RRB-

in

the

present

study

can

be

explained

by

the

smaller

number

of

patients

and/or

patient

selection

However

it

may

well

be

related

to

the

smaller

magnitude

of

the

operation

and

the

corresponding

decreased

operation

time

and

blood

loss

Median

hospital

stay

was

days

-LRB-

range

-RRB-

which

was

also

shorter

than

the

and

days

in

the

aforementioned

studies

Hepatic

toxicity

is

remarkably

low

in

the

present

series

except

for

three

patients

who

developed

bile

duct

necrosis

-LRB-

Table

-RRB-

High

peak

concentrations

of

melphalan

in

the

isolated

circuit

might

explain

the

bile

duct

necrosis

that

was

observed

in

patients

who

were

perfused

with

higher

melphalan

concentrations

In

a

preclinical

study

the

occurrence

of

severe

cholangiofibrosis

was

strongly

dependent

on

the

melphalan

concentration

The

study

also

demonstrated

that

tumor

response

was

not

affected

by

melphalan

peak

concentration

but

by

the

total

dose

of

melphalan

Therefore

to

prevent

high

peak

concentrations

keeping

the

same

concentration

of

melphalan

bolus

infusions

were

replaced

by

a

pump

infusion

This

resulted

in

the

absence

of

bile

duct

necrosis

in

the

last

perfused

patients

The

maximum

period

of

hypoxia

did

not

seem

to

result

in

extrahepatic

and/or

systemic

toxicity

Moreover

clamping

of

the

aorta

just

underneath

the

diaphragm

for

a

maximum

of

minutes

did

not

lead

to

renal

and/or

gastrointestinal

morbidity

To

overcome

the

use

of

a

venovenous

bypass

and

heart-lung

machine

we

performed

a

hypoxic

perfusion

The

use

of

hypoxia

might

also

enhance

the

antitumor

effect

Hypoxia

renders

tumor

cells

more

sensitive

to

cytostatic

agents

in

general

and

enhances

the

antitumor

effects

of

drugs

such

as

melphalan

Changing

the

perfusion

direction

may

reduce

liver

toxicity

without

affecting

the

antitumor

efficacy

as

described

by

Rothbarth

et

al.

An

animal

study

demonstrated

an

unaffected

tumor

uptake

and

a

reduced

liver

uptake

by

in

an

IHP

model

with

arterial

inflow

and

retrograde

portal

outflow

This

may

explain

our

remarkably

low

hepatic

toxicity

in

the

present

series

using

retrograde

outflow

in

a

clinical

setting

In

the

large

IHP

series

of

patients

with

colorectal

liver

metastasis

response

rates

of

and

respectively

are

reported

which

is

in

line

with

the

response

rate

in

the

present

study

The

median

time

to

progression

in

these

IHP

studies

was

and

months

respectively

The

time

to

tumor

progression

of

months

after

IHHP

seems

to

be

comparable

to

these

numbers

Alexander

et

al.

published

their

results

in

patients

with

progressive

disease

after

irinotecan-based

therapies

and

still

a

response

rate

of

was

obtained

after

IHP

with

melphalan

The

survival

was

with

a

median

survival

Although

interpretation

and

comparison

of

the

results

from

these

different

studies

are

difficult

the

results

of

the

retrograde

IHHP

technique

described

here

are

similar

In

the

past

years

new

anticancer

agents

-LRB-

oxaliplatin

and

irinotecan

-RRB-

have

increased

the

response

and

survival

rates

The

addition

of

targeted

therapies

-LRB-

cetuximab

and

bevacuzimab

-RRB-

may

increase

the

response

rates

more

than

Especially

in

this

era

of

exciting

developments

tailored

treatment

to

increase

individual

survival

rates

while

keeping

the

toxic

effects

to

a

minimum

is

challenging

The

role

of

IHP

in

colorectal

liver

metastases

has

been

discussed

in

recent

reviews

The

promising

results

of

the

IHP

studies

in

the

past

years

can

not

be

disregarded

It

is

conceivable

to

combine

IHP

with

adjuvant

treatment

strategies

to

reduce

the

recurrence

rate

which

is

the

major

determinant

of

the

survival

rate

after

IHP

Continuing

locoregional

treatment

by

HAI

after

an

IHP

procedure

is

technically

feasible

and

appears

to

prolong

the

duration

of

the

response

and

survival

in

patients

with

colorectal

hepatic

metastases

Of

the

patients

with

colorectal

liver

metastases

in

the

present

series

developed

extrahepatic

disease

suggesting

the

need

for

additional

systemic

treatment

Duration

of

tumor

control

needs

to

be

improved

To

achieve

this

the

addition

of

vasoactive

drugs

identified

in

our

laboratory

to

have

synergistic

activity

in

combination

with

melphalan

by

significantly

increasing

drug

uptake

in

the

metastases

will

be

explored

in

further

studies

At

this

time

IHHP

should

be

reserved

for

those

patients

who

are

progressive

on

standard

chemotherapy

protocols

When

responses

in

future

trials

are

improved

this

technique

might

be

optional

for

patients

who

prefer

a

single

procedure

which

could

potentially

lead

to

similar

results

as

multiple

courses

of

systemic

or

intra-arterial

chemotherapy

Leaving

behind

at

the

end

of

the

IHHP

a

port-a-cath

system

for

subsequent

HAI

in

case

of

-LRB-

re

-RRB-

progression

should

also

be

considered

as

a

strategy

to

further

improve

prolonged

locoregional

tumor

control

In

ocular

melanoma

the

liver

is

the

only

organ

site

involved

in

of

patients

and

is

usually

responsible

for

death

The

prognosis

of

a

patient

with

hepatic

metastases

from

uveal

melanoma

is

extremely

poor

with

a

median

survival

between

and

months

Partial

liver

resection

is

seldom

possible

The

therapeutic

options

are

not

very

effective

with

systemic

chemotherapy

providing

partial

responses

and

no

survival

benefit

There

is

limited

experience

with

IHP

for

hepatic

metastases

from

uveal

melanoma

but

the

response

rates

are

promising

Despite

the

fact

that

the

experience

with

hepatic

metastases

from

uveal

melanoma

is

small

in

the

present

study

-LRB-

n

-RRB-

IHP

seems

to

be

an

effective

treatment

All

four

patients

died

because

of

progressive

tumor

growth

and

consequent

liver

failure

after

and

months

Therefore

especially

in

this

group

of

patients

local

tumor

control

is

likely

to

result

in

a

survival

benefit

CONCLUSIONS

Isolated

hypoxic

hepatic

perfusion

with

retrograde

outflow

via

portal

vein

is

a

promising

technique

that

is

a

relatively

simple

procedure

with

reduced

blood

loss

no

mortality

very

limited

toxicity

and

response

rates

comparable

to

classic

extensive

IHP

The

operation

time

is

reduced

to

hours

without

the

need

of

a

heart-lung

machine

and

perfusionists

which

reduces

the

costs

O B O O O B I O O O O O O O O O O O O B I I O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O B O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O B O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O B O O O O O O O O O B O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O

isolated hepatic perfusion
retrograde outflow
hypoxic
metastasis
melphalan


An X-ray template assessment for distal radial fractures Background The current method for radiological measurements on plain X-rays of distal radius fractures is unreliable . We examined the reproducibility of a new X-ray assessment technique -- where the uninjured side is used as a template for the injured side -- compared to the conventional assessment technique . Introduction The important factors for decision-making in the treatment of distal radial fractures include the patient 's vitality , fracture classification , fracture dislocation and soft tissue condition . Distal radial fracture deformities are quantified by X-ray measurements which are also used to classify the result after reduction -LRB- e.g. , good or fair result -RRB- -LSB- 1 , 2 -RSB- . However , the clinical usefulness of X-ray measurements is hampered by their limited reproducibility -LSB- 3 , 4 -RSB- . It is also recognized that the modest reproducibility of X-ray deformations is one of the keystones for the lack of reproducibility in the treatment of distal radial fractures -LSB- 3 -- 5 -RSB- . Clearly , when measurements can not be made reliably , a straightforward clinical comparison of treatment techniques or reduction results is impossible , making it difficult to come to level 1 evidence-based treatment results and advices . Other studies that have evaluated sources of variance in the assessment of the quantitative X-ray measurements have reported difficulties with respect to the determination of the radial axis in the anterior -- posterior -LRB- AP -RRB- view , which is essential to assess the radial height and the radial inclination . This is obviously much less a problem in the lateral view , where the higher reproducibility value was found -LSB- 6 -RSB- . A second source of inaccuracy might be the use of the existing normal values for radial length -LRB- 11 mm -RRB- , radial angle -LRB- 22 ° -RRB- and volar angulation -LRB- 10 ° -RRB- -LSB- 7 -- 11 -RSB- , despite the normal variation that exists within the population -LSB- 12 -RSB- . To circumvent these difficulties , we designed a technique to assess fracture deformities of the distal radius that is based on the comparison of the injured side to the uninjured side . The approach is based on research findings that indicate that the patients ' left and right side are comparable -LSB- 13 -RSB- . The aim of the study was to evaluate the reproducibility of the template assessment technique as compared with the direct quantitative measurement technique . We also examined whether the new technique resulted in a more reliable classification of reduction results for distal radius fractures . Materials and methods Inclusion criteria Patients aged 18 years or above with a unilateral dislocated distal radial fracture with the history of neither a distal radial fracture nor a distal radial operation were included after informed consent was taken . A stratification for the AO fracture types was performed to reflect the prevalence in clinical practice at a ratio of 5:2:3 for the AO type A , B and C distal radial fractures . The standard post-reduction -LRB- postero-anterior -LRB- PA -RRB- and lateral -RRB- X-rays and standard distal radius X-rays of the unaffected side of 30 consecutive patients visiting the emergency department were included after stratification for AO fracture type . Eight experienced observers , 4 trauma surgeons , 3 orthopedic surgeons and 1 trauma radiologist , independently measured the X-rays and subsequently classified the reduction results using the Lidström score -LRB- Fig. 1 -RRB- . Fig. 1Anatomical radiological classification for distal radial fractures according to Lidström In the first direct measurement round , the x-rays were only measured quantitatively . The radial length and the radial inclination were measured on the posterior -- anterior plain X-ray film , while the dorsal/volar angulation was measured on the lateral X-ray film . The measurements were performed with a goniometer and a ruler . The normal values for radial length -LRB- 11 mm -RRB- , radial inclination -LRB- 22 ° -RRB- and volar angulation -LRB- 10 ° -RRB- were used to assign a Lidström score -LRB- Fig. 2 -RRB- . Fig. 2Normal value measurement of the distal radius During the second round , scheduled 2 months later , the template measurement technique of comparing the fractured side with the unaffected side was performed by the same observers measuring the X-rays of the same patients . The observers were instructed to assign a Lidström score using the X-rays of the unaffected distal radius as a template for the fractured side -LRB- Fig. 3 -RRB- . The templates of the unaffected side were made by the investigators on transparent sheets , by tracing the distal radius , ulna and first carpal row from the unaffected side plain PA X-Ray film on a overlaid transparent sheet . For the lateral film , only the distal radius and the lunate bone from the unaffected side were drawn on to the overlaid transparent sheet . The reference points on the AP templates were the ulna and/or the first carpal row -LRB- Fig. 3 -RRB- . On the lateral template , the reference points were the radial shaft/and or the lunatum . The measurements again were done with a goniometer and a ruler . And again the results were used to assign a Lidström score . Fig. 3Measurements of distal radial fractures using the unaffected side as template Statistical analysis Overall inter-observer reproducibility of quantitative X-ray measurements for the difference in radial length , radial inclination and volar angulation for the eight observers was estimated using intraclass correlation coefficients -LRB- case 2 , 1 -RRB- -LSB- 14 -RSB- . The reproducibility of the ordinal Lidström scoring was quantified using a weighted kappa coefficient -LRB- Kw -RRB- . Since intraclass correlations -LRB- ICC -RRB- and Kw are computationally equivalent -LSB- 15 -RSB- , both were interpreted using the arbitrary classification proposed by Landis and Koch -LSB- 16 -RSB- : < 0.00 poor ; 0.00 -- 0.20 slight ; 0.21 -- 0.40 fair ; 0.41 -- 0.60 moderate ; 0.61 -- 0.80 substantial and 0.81 -- 1.00 almost perfect agreement . Calculation of the reproducibility coefficients were carried out considering the pair-wise ratings of all possible combinations of observers . For example , observer 1 and 2 , observer 1 and 3 , observer 1 and 4 , and so on to observer 1 and 8 . Then observer 2 and 3 , observer 2 and 4 , observer 2 and 5 and so on to observer 2 and 8 . This was done for each observer to the last observers 7 and 8 . For 8 observers and 30 X-rays this resulted in 28 -LRB- 8 × 7/2 -RRB- possible pairs times 30 X-rays , totalling 840 pairs of observations . Sample size and number of observers were chosen to accommodate the precision of the reproducibility estimates we wanted to achieve . When the number of observations is 840 , a 2-sided 95 % confidence interval -LRB- CI -RRB- for a reproducibility coefficient arbitrarily set at 0.40 will extend 0.05 around the point estimate -LRB- from 0.35 to 0.45 -RRB- . Statistical evaluations were carried out using SPSS 11.5 and StatXact 3.02 for Windows . Results Thirty patients with distal radial fractures were included . Of these patients , 15 fractures were of AO classification group A , 6 AO classification group B and 9 of AO classification group C. Table 1 , shows the reproducibility coefficients for the direct quantitative X-ray measures and the template assessment technique . Slight and insignificant increases in ICCs -LRB- 95 % CI -RRB- were observed for the radial length from 0.53 -LRB- 0.48 / 0.57 -RRB- to 0.54 -LRB- 0.49 / 0.59 -RRB- and volar angulation from 0.60 -LRB- 0.56 / 0.64 -RRB- to 0.64 -LRB- 0.60 / 0.68 -RRB- . Marked improvements in reproducibility were observed for the radial inclination measurements . Intraclass correlations increased from 0.36 -LRB- 0.30 / 0.41 -RRB- with the old technique to 0.49 -LRB- 0.43 / 0.55 -RRB- with the template technique . The overall kappa for the Lidström score in the old technique was 0.37 -LRB- 0.31 / 0.43 -RRB- and improved in the template technique to 0.59 -LRB- 0.52 / 0.63 -RRB- . Table 1Reproducibility coefficients for the X-ray measurements : old direct measurement technique versus template technique -LRB- N = 840 observations -RRB- MeasureaOld technique -LRB- 95 % CI -RRB- Template technique -LRB- 95 % CI -RRB- Radial length 0.53 -LRB- 0.48 / 0.57 -RRB- 0.54 -LRB- 0.49 / 0.59 -RRB- Radial inclination 0.36 -LRB- 0.30 / 0.41 -RRB- 0.49 -LRB- 0.43 / 0.55 -RRB- Volar angulation 0.60 -LRB- 0.56 / 0.64 -RRB- 0.64 -LRB- 0.60 / 0.68 -RRB- Lidström0 .37 -LRB- 0.31 / 0.43 -RRB- 0.59 -LRB- 0.52 / 0.63 -RRB- aCategorical data , weighted kappa , numerical data , ICC Discussion Compared to the traditional quantitative technique , the template assessment technique resulted only in an improved inter-observer reproducibility for the radial inclination . There were slight improvements in reproducibility of the radial length and volar angulation . However , there was a notable improvement in the reproducibility of reduction results as assessed using the Lidström score . The results of the quantative measurements of radial length and radial inclination are comparable to those reported by Kreder et al. . They reported an inter-observer reliability coefficient of 0.49 for the radial length , and 0.32 for the AP radial angle -LSB- 6 -RSB- . As in our study , a better reproducibility was found for the volar angulation on the lateral view . In this comparative study we had the same observers and the same patients with a 2-month interval and X-rays presented in another sequence order to overcome possible bias . The patients ' sample was chosen to reflect the daily practice in which the AO type A fractures are more frequent than the Type B and C . One could argue that the use of normal values for the traditional quantitative measurement technique would negatively affect its reproducibility since there is variation in anatomical proportions between individuals in the population . For example , the ulnar length varies within 30 % of the population -LSB- 12 -RSB- . Therefore , the use of normal values may lead to inaccurate classification of the reduction result . However , in our study , the comparison with the normal values did not negatively influenc the reproducibility , since all observers used the same values . By doing so , the only source of error left was the direct measurement of the fractured side . When the normal side is used to compare with in the classical measurement way , there would be measurement errors of the fractured side and of the uninjured side . The improved reproducibility of the fractures deformity classification as expressed by the Lidström score -LRB- from 0.37 to 0.59 -RRB- was primarily due to improvement in measurement of the radial inclination in the template technique . By using the template technique for the Lidström score , one could expect the most improvements in both the radial length and radial inclinations . The volar angulation would not be expected to improve much since it is measured independently from the other side -LRB- Fig. 1 -RRB- . Surprisingly , we could not demonstrate an influence of the template technique for the radial length in this study , although it is partly dependent on the position of the radial axis on the PA view and could therefore benefit from templating . An explanation for this phenomenon could be that for measuring the difference in radial height -LRB- as shown in Fig. 3 -RRB- , there is still an axis needed . This becomes more eminent as the radial styloid is displaced more laterally -LRB- or rotated -RRB- and both tips of the radial styloid are not in line with the radial axis any more . Differences in placing the axis could be a source for variance , leading to a limited improvement in the Kappa value . In contrast , the radial inclination on the PA view in the template technique is basically independent of the radial axis and therefore more easy to measure with the template . A limitation of the template technique is that it may not be applicable in patients with a bilateral fracture or patients with a history of a distal radial fracture or deformity on the other side . In this study , only patients with a unilateral distal radial fracture were included , reflecting the most common occurrence of distal radial fractures . Another limitation of this study was that , in order to avoid learning curves , only experienced observers were used , which may not always be the case in daily practice . Also , the templates of the unaffected side were made by the same investigator . In daily practice , making the template could also be a source of variation since the correct position of the templates may be more difficult in case of severe dislocation or with slight differences in projection of the bones due to the angle of the X-ray beam . Perhaps the use of digital subtraction may be helpful to overcome this . In conclusion , by using the template technique for X-Ray measurement we improved the reproducibility of the classification of radiological dislocation of distal radius fractures which is a step to come to evidence based distal radial fracture treatment as outlined in two recent Cochrane reviews -LSB- 4 , 5 -RSB- . This procedure can also be performed for other radiological parameters such as ulnar variance . Future research should focus on the improvement of the template technique and the use of digital measurement -- subtraction techniques/software modules in this time of filmless X-Ray pictures .

O O O O O B I I O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O B O O O O O B O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O

radius
classification
distal radial fractures