- Email: [email protected]
Risk factors for incisional hernia after hepatic resection for hepatocellular carcinoma in patients with liver cirrhosis
Risk factors for incisional hernia after hepatic resection for hepatocellular carcinoma in patients with liver cirrhosis Hiroto Kayashima, MD, PhD, Takashi Maeda, MD, PhD, Noboru Harada, MD, PhD, Takanobu Masuda, MD, Atsushi Guntani, MD, PhD, Shuhei Ito, MD, PhD, Ayumi Matsuyama, MD, PhD, Motohiro Hamatake, MD, PhD, Shinichi Tsutsui, MD, PhD, Hiroyuki Matsuda, MD, PhD, and Teruyoshi Ishida, MD, PhD, Hiroshima, Japan
Background. The risk factors for incisional hernia (IH) and the association between liver fibrosis and IH after hepatic resection in patients with hepatocellular carcinoma (HCC) with liver cirrhosis (LC) are still unclear. We aimed to evaluate the rate of IH and to assess the effect of perioperative factors, including serum markers for liver fibrosis, on the risk of IH. Methods. A total of 192 patients with HCC with LC who received hepatectomy were retrospectively analyzed. The primary end point was the incidence rate of IH and the secondary end points were associations between IH and 22 clinical factors. Results. IH was diagnosed in 60 (31.3%) patients. The estimated incidence rates were 19.8% at 12 months, 32.5% at 36 months, and 38.8% at 60 months. In multivariable analysis, the presence of postoperative intractable ascites (odds ratio 24.83, P = .0003), abdominal wall closure by a single-layer mass closure with a continuous running suture (odds ratio 4.59, P = .0143), preoperative body mass index $25 kg/m2 (odds ratio 3.36, P = .0025), and preoperative serum N-terminal pro-peptide of type IV collagen 7S domain (P4NP 7S) levels $5 ng/mL (odds ratio 3.13, P = .0234) were independent risk factors. Conclusion. There are several risk factors for IH after hepatic resection in HCC patients with LC. Preoperative serum P4NP 7S levels $5 ng/mL are a useful predictive marker, and abdominal wall closure with a continuous running suture by a single-layer mass closure should be avoided. (Surgery 2015;158:1669-75.) From the Department of Surgery, Hiroshima Red Cross Hospital and Atomic Bomb Survivors Hospital, Hiroshima, Japan
INCISIONAL HERNIA (IH) is one of the most common postoperative complications after abdominal surgery and often requires reoperation for repair. Various independent risk factors for IH have been reported in previous studies, including advanced age, sex, high body mass index (BMI), nutritional status, diabetes mellitus, current smoking, chronic obstructive pulmonary disease, systemic use of corticosteroids, diagnosis of cancer, previous laparotomy, emergency surgery, duration Accepted for publication June 1, 2015. Reprint requests: Hiroto Kayashima, MD, PhD, Department of Surgery, Hiroshima Red Cross Hospital and Atomic Bomb Survivors Hospital, 1-9-6 Senda-cho, Naka-ku, Hiroshima 7308619, Japan. E-mail: [email protected]. 0039-6060/$ - see front matter Ó 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.surg.2015.06.001
of surgery, incision type, blood transfusion, optimal method and material for abdominal closure, and surgical-site infection (SSI).1-10 The rate of IH 1 year after the operation is between 9 and 20%.11 Furthermore, the 10-year cumulative recurrence rate after IH repair is 63% and 32% for suture and mesh repair, respectively.12 IH results in an impaired quality of life and increased costs of treatment for patients; therefore, the prevention of IH is important. There are only 2 reports of IH after hepatic resection.13,14 These reports describe that the risk factors for IH after partial hepatectomy are type of incision, postoperative ascites, repeat hepatectomy, corticosteroid use, age, sex, and BMI in multivariate analysis. These studies included patients with hepatocellular carcinoma (HCC) and liver metastasis (LM); however, these 2 groups have entirely different conditions of the liver. SURGERY 1669
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Generally, patients with HCC have liver dysfunction as the result of liver cirrhosis (LC). LC is the end stage of many forms of chronic hepatitis of different etiologies. LC is a diffuse process characterized by fibrosis and conversion of normal liver architecture into structurally abnormal nodules surrounded by annular fibrosis. This chronic progressive clinical condition leads to liver cell failure, portal hypertension, gut dysfunction, nutritional disorders, immune dysfunction, and delayed wound healing.15-18 Clinically, LC is divided into 2 phases: compensated and decompensated.19 Decompensated LC is easily diagnosed because it presents with a series of clinical and laboratory signs and is excluded from the indication of hepatic resection. In compensated LC, the degree of liver fibrosis is difficult to assess in accurate detail for indication of surgery. Liver biopsy currently is considered the best-available standard of reference, but it has some limits. Therefore, alternative noninvasive serum markers, including transferrin, N-terminal pro-peptide of type IV collagen 7S domain (P4NP 7S), and hyaluronic acid, have been developed to substitute liver biopsies when assessing liver fibrosis.15,20 The specific risk factors for IH and the association between liver fibrosis and IH after hepatic resection in HCC patients with LC are still unclear. We hypothesized that HCC patients with LC have a greater risk of IH and that the severity of liver fibrosis is strongly correlated with the development of IH. The purpose of the present study was to evaluate the rate of IH after hepatic resection and to assess the effect of perioperative factors, including some serum markers for liver fibrosis, on the risk of IH in HCC patients with LC. PATIENTS AND METHODS Patients. Between April 2009 and March 2013, 251 consecutive patients with LC who underwent elective hepatic resection for HCC at the Hiroshima Red Cross Hospital and Atomic Bomb Survivors Hospital were enrolled in this study. Written informed consent was obtained from all patients for operative treatment according to institutional guidelines. The study protocol conformed to the updated ethical guidelines of the 2013 Declaration of Helsinki and was approved by our institutional review board. One patient had hepatic resection in combination with bowel resection, and in one patient, only a purely laparoscopic operation was performed with port-site wounds. Within 12 months after surgery, 15 patients died, 14 patients underwent re-laparotomy, and 28 patients
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were lost to follow-up. These 59 patients were excluded from this study. End points. The primary end point of this study was the incident rate of IH. The secondary end points were associations between IH and 22 clinical factors. Type of incision. The definitions of the type of incision for hepatic resection have been described elsewhere.13,14 To summarize, a J-shaped incision involved an extended right subcostal incision with a vertical midline extension. A ‘‘Mercedes’’ incision involved a bilateral subcostal incision with a vertical midline extension. The type of incision was determined by the location and size of HCC. Operative procedure. The hepatic resections that were performed were defined according to the Couinaud classification. Liver resections combined with vascular resection, diaphragmatic resection, or additional ablations were included. In principle, hepatic resection was performed with intermittent inflow occlusion, except for severe adhesion. This maneuver frequently is used in liver surgery to control bleeding when dividing the liver parenchyma by clamping the hepatoduodenal ligament and interrupting the flow of blood through the hepatic artery and the portal vein. The routine administration of prophylactic antibiotics was performed just before the operation and then usually continued for 48–72 hr after surgery. Method of abdominal wall closure. Closure of the abdominal wall muscle and fascia was performed in a single-layer mass closure with no. 1 absorbable monofilament Biosyn loops with a continuous running suture (Nippon Covidien Inc, Tokyo, Japan) or with no. 1 absorbable braid Vicryl interrupted sutures (Johnson & Johnson K. K., Tokyo, Japan). Skin closure was performed with subcuticular closure using a running 4-0 absorbable monofilament PDS suture (Johnson & Johnson K. K.) with a subcutaneous drainage tube. Diagnosis of IH. The definition of IH after hepatic resection has been previously described.13,14 IH was diagnosed on the basis of computed tomography (CT) findings. Generally, a hernia is defined as a protrusion that is covered with the peritoneum and protrudes from the abdominal wall. In this study, when fascial discontinuity of the abdominal wall was demonstrated by CT findings, the case was included in IH. A diagnosis of ‘‘no hernia’’ required a minimum followup of 12 months. Monitored perioperative factors. Preoperative factors included age, sex, BMI, diabetes mellitus, current smoking, Child–Pugh score, liver damage
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classification, number of platelets, indocyanine green retention test at 15 minutes (ICG15R), serum transferrin levels, serum prealbumin levels, serum P4NP 7S levels, and serum hyaluronic acid levels. Operative factors included repeat hepatectomy, duration of the operation, blood loss, intraoperative blood transfusion, type of incision, and method of abdominal wall closure. Postoperative factors included histopathologic status of the noncancerous part of the liver, SSI, and postoperative intractable ascites. Ascites was considered intractable when definitely observed by CT more than 1 month after surgery, despite diuretic administration. Statistical analysis. Data are expressed as the mean ± SD. Continuous variables were evaluated using the Student t test or the Wilcoxon rank-sum test. Categorical data were compared using the v2 test or Fisher exact test. To identify the independent risk factors of IH, the factors that were significant with univariable analysis were subjected to multivariable analysis by the use of logistic regression analysis. Incidence rates for IH were calculated by means of the Kaplan–Meier method for estimating crude risk using the date of diagnosis of IH. All analyses were performed with the use of JMP Pro software (Version 11.0, SAS Institute Japan Ltd, Tokyo, Japan). RESULTS Patients’ characteristics and the incidence rate of IH. From April 2009 to March 2013, hepatic resection for HCC was performed in 251 consecutive patients with LC, and 192 (76.5%) of these patients met the inclusion criteria of this study. In 42 (21.9%) patients who died more than 12 months after surgery, evaluation of IH was performed at least once before death. The median length of follow-up for IH was 27 months (range, 1–64 months). Of these 192 patients, 116 (60.4%) had hepatitis C virus infection, 35 (18.2%) had hepatitis B virus infection, 1 (0.5%) had both hepatitis C and B virus infections, and 40 (20.8%) had no infection. A total of 167 (87.0%) patients received open abdominal surgery, and 25 (13.0%) had laparoscopic-assisted surgery. A total of 152 (79.2%) patients had a J-shaped incision, 19 (9.9%) had a median incision, 14 (7.3%) had a right subcostal incision, and 7 (3.6%) had a ‘‘Mercedes’’ incision. In total, IH occurred in 60 (31.3%) patients. Among these 60 patients, the site of hernias was the lateral area in 33 (55.0%), the trifurcation area in 15 (25.0%), the median area in 9 (15.0%), and all 3 areas in 3 (5.0%) patients. The Kaplan–Meier estimated incidence rates of IH
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Fig 1. Kaplan–Meier analysis of the rate of IH after hepatic resection for HCC in patients with LC. Incidence rates for IH were calculated by the Kaplan–Meier method for estimating crude risk using the date of diagnosis of IH. The estimated incidence rates of IH were 19.8% at 12 months, 28.7% at 24 months, 32.5% at 36 months, 34.0% at 48 months, and 38.8% at 60 months.
were 19.8% at 12 months, 28.7% at 24 months, 32.5% at 36 months, 34.0% at 48 months, and 38.8% at 60 months (Fig 1). Univariable analysis. Table I shows univariable analysis of the association of risk factors with development of IH. Among 22 possible risk factors (including 13 preoperative, 6 intraoperative and 3 postoperative factors), 12 of these were significant as follows: BMI (P = .0058), Child–Pugh score (P = .0078), liver damage classification (P = .0247), number of platelets (P = .0021), ICG15R (P = .0046), serum P4NP 7S levels (P = .0006), serum hyaluronic acid levels (P = .0299), intraoperative blood transfusion (P = .0124), method of abdominal wall closure (P = .0388), histopathologic status of the noncancerous part of the liver (P = .0019), SSI (P = .0124), and postoperative intractable ascites (P < .0001). Multivariable analysis. To identify the independent risk factors of IH, the 12 factors that were significant in univariable analysis were subjected to multivariable analysis using logistic regression analysis. Continuous variables were divided into two groups using the cutoff point calculated by a receiver operating characteristic (ROC) curve (Fig 2). Four independent risk factors for IH were identified (Table II), including the presence of postoperative intractable ascites (odds ratio 24.83, P = .0003), abdominal wall closure by a singlelayer mass closure with a continuous running suture (odds ratio 4.59, P = .0143), preoperative BMI $25 kg/m2 (odds ratio 3.36, P = .0025), and
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Table I. Univariable analysis of risk factors for IH after hepatic resection for hepatocellular carcinoma in patients with LC Variables Preoperative factors Age Sex, male/female DM, yes/no Current smoking, yes/no BMI, kg/m2 Child-Pugh score, 5/6 and 7 Liver damage classification, A/B Platelets, 104/mL ICG15R, % P4NP 7S, ng/mL Hyaluronic acid, ng/mL Transferrin, mg/dL Prealbumin, mg/dL Intraoperative factors Repeat hepatectomy, yes/no Duration of operation, min Blood loss, mL Blood transfusion, yes/no Incision type, J-shaped/median/subcostal/Mercedes Abdominal wall closure, continuous/intermittent Postoperative factors Histopathologic status of noncancerous liver, LC/pre-LC SSI, yes/no Intractable ascites, yes/no
IH (+) group (n = 60)
IH ( ) group (n = 132)
P value
70.0 ± 7.3 41/19 17/43 10/50 24.4 ± 3.6 42/18 50/10 13.2 ± 7.8 22.9 ± 11.3 7.2 ± 6.4 244.3 ± 279.6 265.9 ± 61.2 18.4 ± 6.6
69.7 ± 9.3 92/40 54/78 31/101 23.0 ± 3.0 117/15 124/8 15.6 ± 6.8 18.5 ± 10.7 5.6 ± 1.7 181.6 ± 258.2 268.6 ± 54.1 19.7 ± 6.6
.8069 .8497 .0905 .2898 .0058 .0078 .0247 .0021 .0046 .0006 .0299 .7602 .1987
18/42 255.9 ± 100.0 531.4 ± 585.7 15/45 101/16/11/4 55/4*
53/79 244.4 ± 92.2 406.4 ± 558.0 14/118 51/3/3/3 109/23
.1730 .4364 .1685 .0124 .2776 .0388
39/21 15/45 10/50
54/78 14/118 1/131
.0019 .0124 <.001
*One operative record did not describe the method of abdominal closure. BMI, Body mass index; DM, diabetes mellitus; ICG15R, indocyanine green retention test at 15 minutes; IH, incisional hernia; LC, liver cirrhosis; P4NP 7S, N-terminal pro-peptide of type IV collagen 7S domain; SSI, surgical-site infection.
preoperative serum P4NP 7S levels $5 ng/mL (odds ratio 3.13, P = .0234). DISCUSSION IH is one of the most common complications after abdominal surgery. As many as 80–95% of patients with IH develop this complication within 6–36 months after the initial operation.4 Indeed, in our study, the rates of the incidence of IH increased progressively until 36 months postoperatively and then generally continued to plateau. Prevention of development of IH is important to avoid suffering in patients and to reduce medical treatment costs for the welfare system. Liver resection sometimes requires a wide incision be made. Many patients who undergo hepatectomy are concerned about wound complications, especially IH. In our study, there were no significant differences in incision type, repeat hepatectomy, age, and sex between the IH (+) and IH ( ) groups. This study included only HCC patients with LC because conditions of the liver are different between patients with HCC
versus LM. Generally, patients with HCC have severe liver dysfunction with various degrees of liver fibrosis due to LC. Liver fibrosis is diagnosed by histologic analysis of liver biopsy specimens. However, liver biopsy is invasive and is limited by sampling errors, diagnostic inaccuracy, and hazards to the patient. Therefore, to assess the degree of liver fibrosis, alternative noninvasive serum markers, including transferrin, P4NP 7S, and hyaluronic acid, are tested preoperatively.15,20 Type IV collagen is the most important structural component of the basement membrane, which constitutes one part of the extracellular matrix. P4NP is known to self-assemble into a polymer and has a network-like structure consisting of a 7S domain complex with helix regions. This structure is only soluble and unmasked after digestion by pepsin in a healthy state. After pepsin pretreatment of type IV collagen, it becomes soluble and available (eg, gelatinase cleavage). When the liver becomes fibrotic, stellate cells and lipocytes start to deposit basement membrane proteins, such as laminin and type IV collagen, around
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Fig 2. ROC curves for the development of IH after hepatic resection for HCC in patients with LC. The optimal cutoff thresholds of BMI, serum P4NP 7S levels, ICG15R, number of platelets, and serum hyaluronic acid levels were calculated by ROC curve. (A) BMI. The area under the ROC curve (AUC) was 0.6244. The optimal cutoff threshold was 25 kg/m2. (B) P4NP 7S levels. The AUC was 0.6551. The optimal cutoff threshold was 5 ng/mL. (C) ICG15R. The AUC was 0.6278. The optimal cutoff threshold was 15%. (D) Number of platelets. The AUC was 0.6386. The optimal cutoff threshold was 14 3 104/mL. (E) Serum hyaluronic acid levels. The AUC was 0.5981. The optimal cutoff threshold was 120 ng/mL.
Table II. Multivariable analysis of risk factors for IH after hepatic resection for hepatocellular carcinoma in patients with LC Variable
Parameter
Odds ratio
95% CI
P value
Intractable ascites BMI, kg/m2 Abdominal wall closure P4NP 7S, ng/mL ICG15R, % Child-Pugh score Platelets, 104/mL SSI Histopathologic status of noncancerous liver Liver damage classification Blood transfusion Hyaluronic acid, ng/mL
Yes $25 Continuous $5 $15 6 and 7 <14 Yes LC B Yes $120
24.83 3.36 4.59 3.13 2.09 2.48 1.31 1.36 0.86 0.92 1.03 1.00
3.78–500.93 1.53–7.59 1.33–20.77 1.16–9.12 0.89–5.09 0.81–7.77 0.57–3.03 0.49–3.67 0.35–2.06 0.23–3.69 0.36–2.85 0.42–2.38
.0003 .0025 .0143 .0234 .0889 .1126 .5282 .5431 .7418 .9225 .9568 .9987
BMI, Body mass index; CI, confidence interval; ICG15R, indocyanine green retention test at 15 minutes; IH, incisional hernia; LC, liver cirrhosis; P4NP 7S, N-terminal pro-peptide of type IV collagen 7S domain; SSI, surgical-site infection.
the subendothelial sinusoids and in the space of Disse, which contributes to impaired hepatocellular function. Therefore, P4NP 7S is a potential biochemical marker for basement
membrane turnover during liver fibrosis and reflects the abnormality of type IV collagen.21 Collagen metabolism in patients with a hernia is altered at 3 levels: the type I/III collagen ratio is
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decreased, the quality of collagen is poorer, and collagen breakdown is increased.22 Studies on skin and fascia samples from patients with IH have shown a significantly decreased ratio of type I/III collagen and type I/III procollagen mRNA compared with controls.23-27 This lower ratio is caused by an increase in the amount of type III collagen in patients with IH. Furthermore, some of these reports have described that patients with IH have systemically altered type IV collagen metabolism. Salameh et al25 reported that type V collagen is not altered, whereas type IV collagen appears to be undetectable in fascia of patients with IH. Another study reported that overexpression of the gene coding for collagen type IV is found in the skin of patients with recurrent IH.26 Recently, Henriksen et al27 reported that synthesis of type IV collagen was increased in patients with IH and the best model for predicting the presence of hernias included the turnover of type IV collagen. These results suggest that, even though a hernia presents as a local phenomenon, formation of a hernia is a systemic disease, and a systemically altered quality of type IV collagen may lead to a greater risk of formation of hernias. In our study, preoperative serum P4NP 7S levels $5 ng/ mL were an independent risk factor for IH. This result suggests that abnormality of type IV collagen might be not only a consequence of liver fibrosis but also the cause of IH. Risk factors can be divided into patient- and surgeon-related factors. Although patient-related factors cannot be controlled, surgeon-related factors (eg, the choice of suture material, the method of abdominal wall closure, and the quality of the suture technique) can be controlled entirely by the surgeon. Our study showed that abdominal wall closure by a single-layer mass closure with a continuous running suture was an independent risk factor for IH. One of the reasons for this finding might be that no. 1 absorbable monofilament Biosyn loops, the suture material used in this study, does not have sufficient tensile strength retention. Generally, a normally healed wound has gained 50% of its original strength after approximately 6 weeks.28 According to the product document, the breaking strength retention after 3 weeks of no. 1 absorbable monofilament Biosyn loops is approximately 40%, and this suture material is almost completely absorbed after approximately 90–110 days. Other suture material with a more powerful and prolonged tensile strength retention should be used. In conclusion, although there are several risk factors for IH after hepatic resection in HCC
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patients with LC, preoperative serum P4NP 7S levels $5 ng/mL are a useful predictive marker for the development of IH, and abdominal wall closure with a continuous running suture by a single-layer mass closure should be avoided to prevent IH. REFERENCES 1. Nicolle LE, Huchcroft SA, Cruse PJ. Risk factors for surgical wound infection among elderly. J Clin Epidemiol 1992;45: 357-64. 2. Llaguna OH, Avgerinos DV, Lugo JZ, Matatov T, Abbadessa B, Martz JE, et al. Incidence and risk factors for the development of incisional hernia following elective laparoscopic versus open colon resections. Am J Surg 2010;200:265-9. 3. Bucknall TE, Cox PJ, Ellis H. Burst abdomen and incisional hernia: a prospective study of 1129 major laparotomies. Br Med J (Clin Res Ed) 1982;284:931-3. 4. Mudge M, Hughes LE. Incisional hernia: a 10 year prospective study of incidence and attitudes. Br J Surg 1985;72:70-1. 5. Veljkovic R, Protic M, Gluhovic A, Potic Z, Milosevic Z, Stojadinovic A. Prospective clinical trial of factors predicting the early development of incisional hernia after midline laparotomy. J Am Coll Surg 2010;210:210-9. 6. Laurent C, Leblanc F, Bretagnol F, Capdepont M, Rullier E. Long-term wound advantages of the laparoscopic approach in rectal cancer. Br J Surg 2008;95:903-8. 7. Gruppo M, Mazzalai F, Lorenzetti R, Piatto G, Toniato A, Ballotta E. Midline abdominal wall incisional hernia after aortic reconstructive surgery: a prospective study. Surgery 2012;151:882-8. 8. Seilar CM, Deckert A, Diener MK, Knaebel HP, Weigand MA, Victor N, et al. Midline versus transverse incision in major abdominal surgery: a randomized, doubleblind equivalence trial (POVATI: ISRCTN60734227). Ann Surg 2009;249:913-20. 9. Taylor GW, Jayne DG, Brown SR, Thorpe H, Brown JM, Dewberry SC, et al. Adhesions and incisional hernias following laparoscopic versus open surgery for colorectal cancer in the CLASICC trial. Br J Surg 2010;97:70-8. 10. Itatsu K, Yokoyama Y, Sugawara G, Kubota H, Tojima Y, Kurumiya Y, et al. Incidence of and risk factors for incisional hernia after abdominal surgery. Br J Surg 2014;101:1439-47. 11. Diener MK, Voss S, Jensen K, Buchler MW, Seiler CM. Elective midline laparotomy closure: the INLINE systematic review and meta- analysis. Ann Surg 2010;251:843-56. 12. Burger JW, Luijendijk RW, Hop WC, Halm JA, Verdaasdonk EG, Jeekel J. Long-term follow-up of a randomized controlled trial of suture versus mesh repair of incisional hernia. Ann Surg 2004;240:578-85. 13. Togo S, Nagano Y, Matsumoto C, Takakura H, Matsuo K, Takeda K, et al. Outcome of and risk factors for incisional hernia after partial hepatectomy. J Gastrointest Surg 2008; 12:1115-20. 14. D’Angelica M, Maddineni S, Fong Y, Martin RC, Cohen MS, Ben-Porat L, et al. Optimal abdominal incision for partial hepatectomy: increased late complications with Mercedestype incisions compared to extended right subcostal incisions. World J Surg 2006;30:410-8. 15. Soresi M, Giannitrapani L, Cervello M, Licata A, Montalto G. Non invasive tools for the diagnosis of liver cirrhosis. World J Gastroenterol 2014;20:18131-50. 16. Kalaitzakis E. Gastrointestinal dysfunction in liver cirrhosis. World J Gastroenterol 2014;20:14686-95.
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17. Hanai T, Shiraki M, Nishimura K, Ohnishi S, Imai K, Suetsugu A, et al. Sarcopenia impairs prognosis of patients with liver cirrhosis. Nutrition 2015;31:193-9. 18. Bonnel AR, Bunchorntavakul C, Reddy KR. Immune dysfunction and infection in patients with cirrhosis. Clin Gastroenterol Hepatol 2011;9:727-38. 19. Garcia-Tsao G, Friedman S, Iredale J, Pinzani M. Now there are many (stages) where before there was one: In search of a pathophysiological classification of cirrhosis. Hepatology 2010;51:1445-9. 20. Cho HJ, Kim SS, Ahn SJ, Park JH, Kim DJ, Kim YB, et al. Serum transferrin as a liver fibrosis biomarker in patients with chronic hepatitis B. Clin Mol Hepatol 2014;20:347-54. 21. Leeming DJ, Nielsen MJ, Dai Y, Veidal SS, Vassiliadis E, Zhang C, et al. Enzyme-linked immunosorbent serum assay specific for the 7S domain of Collagen Type IV (P4NP 7S): A marker related to the extracellular matrix remodeling during liver fibrogenesis. Hepatol Res 2012;42:482-93. 22. Henriksen NA, Yadete DH, Srensen LT, Agren MS, Jogensen LN. Connective tissue alternation in abdominal wall hernia. Br J Surg 2011;98:210-9.
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23. Si Z, Bhardwaj R, Rosch R, Mertens PR, Klosterhalfen B, Klinge U. Impaired balance of type I and type III procollagen mRNA in cultured fibroblasts of patients with incisional hernia. Surgery 2002;131:324-31. 24. White B, Osier C, Gletsu N, Jeansonne L, Baghai M, Sherman M, et al. Abnormal primary tissue collagen composition in the skin of recurrent incisional hernia patients. Am Surg 2007;73:1254-8. 25. Salameh JR, Talbott LM, May W, Gosheh B, Vig PJ, McDaniel DO. Role of biomarkers in incisional hernias. Am Surg 2007;73:561-8. 26. Galaluce R, Davis JW, Bachman SL, Gubin MM, Brown JA, Magee JD, et al. Incisional hernia recurrence through genomic profiling: a pilot study. Hernia 2013;17:193-202. 27. Henriksen NA, Mortensen JH, Sorensen LT, Bay-Jensen AC, Agren MS, Jorgensen LN, et al. The collagen turnover profile is altered in patients with inguinal and incisional hernia. Surgery 2015;157:312-21. 28. Israelsson LA, Millbourn D. Prevention of incisional hernias: how to close a midline incision. Surg Clin North Am 2013;93:1027-40.
Background. The risk factors for incisional hernia (IH) and the association between liver fibrosis and IH after hepatic resection in patients with hepatocellular carcinoma (HCC) with liver cirrhosis (LC) are still unclear. We aimed to evaluate the rate of IH and to assess the effect of perioperative factors, including serum markers for liver fibrosis, on the risk of IH. Methods. A total of 192 patients with HCC with LC who received hepatectomy were retrospectively analyzed. The primary end point was the incidence rate of IH and the secondary end points were associations between IH and 22 clinical factors. Results. IH was diagnosed in 60 (31.3%) patients. The estimated incidence rates were 19.8% at 12 months, 32.5% at 36 months, and 38.8% at 60 months. In multivariable analysis, the presence of postoperative intractable ascites (odds ratio 24.83, P = .0003), abdominal wall closure by a single-layer mass closure with a continuous running suture (odds ratio 4.59, P = .0143), preoperative body mass index $25 kg/m2 (odds ratio 3.36, P = .0025), and preoperative serum N-terminal pro-peptide of type IV collagen 7S domain (P4NP 7S) levels $5 ng/mL (odds ratio 3.13, P = .0234) were independent risk factors. Conclusion. There are several risk factors for IH after hepatic resection in HCC patients with LC. Preoperative serum P4NP 7S levels $5 ng/mL are a useful predictive marker, and abdominal wall closure with a continuous running suture by a single-layer mass closure should be avoided. (Surgery 2015;158:1669-75.) From the Department of Surgery, Hiroshima Red Cross Hospital and Atomic Bomb Survivors Hospital, Hiroshima, Japan
INCISIONAL HERNIA (IH) is one of the most common postoperative complications after abdominal surgery and often requires reoperation for repair. Various independent risk factors for IH have been reported in previous studies, including advanced age, sex, high body mass index (BMI), nutritional status, diabetes mellitus, current smoking, chronic obstructive pulmonary disease, systemic use of corticosteroids, diagnosis of cancer, previous laparotomy, emergency surgery, duration Accepted for publication June 1, 2015. Reprint requests: Hiroto Kayashima, MD, PhD, Department of Surgery, Hiroshima Red Cross Hospital and Atomic Bomb Survivors Hospital, 1-9-6 Senda-cho, Naka-ku, Hiroshima 7308619, Japan. E-mail: [email protected]. 0039-6060/$ - see front matter Ó 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.surg.2015.06.001
of surgery, incision type, blood transfusion, optimal method and material for abdominal closure, and surgical-site infection (SSI).1-10 The rate of IH 1 year after the operation is between 9 and 20%.11 Furthermore, the 10-year cumulative recurrence rate after IH repair is 63% and 32% for suture and mesh repair, respectively.12 IH results in an impaired quality of life and increased costs of treatment for patients; therefore, the prevention of IH is important. There are only 2 reports of IH after hepatic resection.13,14 These reports describe that the risk factors for IH after partial hepatectomy are type of incision, postoperative ascites, repeat hepatectomy, corticosteroid use, age, sex, and BMI in multivariate analysis. These studies included patients with hepatocellular carcinoma (HCC) and liver metastasis (LM); however, these 2 groups have entirely different conditions of the liver. SURGERY 1669
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Generally, patients with HCC have liver dysfunction as the result of liver cirrhosis (LC). LC is the end stage of many forms of chronic hepatitis of different etiologies. LC is a diffuse process characterized by fibrosis and conversion of normal liver architecture into structurally abnormal nodules surrounded by annular fibrosis. This chronic progressive clinical condition leads to liver cell failure, portal hypertension, gut dysfunction, nutritional disorders, immune dysfunction, and delayed wound healing.15-18 Clinically, LC is divided into 2 phases: compensated and decompensated.19 Decompensated LC is easily diagnosed because it presents with a series of clinical and laboratory signs and is excluded from the indication of hepatic resection. In compensated LC, the degree of liver fibrosis is difficult to assess in accurate detail for indication of surgery. Liver biopsy currently is considered the best-available standard of reference, but it has some limits. Therefore, alternative noninvasive serum markers, including transferrin, N-terminal pro-peptide of type IV collagen 7S domain (P4NP 7S), and hyaluronic acid, have been developed to substitute liver biopsies when assessing liver fibrosis.15,20 The specific risk factors for IH and the association between liver fibrosis and IH after hepatic resection in HCC patients with LC are still unclear. We hypothesized that HCC patients with LC have a greater risk of IH and that the severity of liver fibrosis is strongly correlated with the development of IH. The purpose of the present study was to evaluate the rate of IH after hepatic resection and to assess the effect of perioperative factors, including some serum markers for liver fibrosis, on the risk of IH in HCC patients with LC. PATIENTS AND METHODS Patients. Between April 2009 and March 2013, 251 consecutive patients with LC who underwent elective hepatic resection for HCC at the Hiroshima Red Cross Hospital and Atomic Bomb Survivors Hospital were enrolled in this study. Written informed consent was obtained from all patients for operative treatment according to institutional guidelines. The study protocol conformed to the updated ethical guidelines of the 2013 Declaration of Helsinki and was approved by our institutional review board. One patient had hepatic resection in combination with bowel resection, and in one patient, only a purely laparoscopic operation was performed with port-site wounds. Within 12 months after surgery, 15 patients died, 14 patients underwent re-laparotomy, and 28 patients
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were lost to follow-up. These 59 patients were excluded from this study. End points. The primary end point of this study was the incident rate of IH. The secondary end points were associations between IH and 22 clinical factors. Type of incision. The definitions of the type of incision for hepatic resection have been described elsewhere.13,14 To summarize, a J-shaped incision involved an extended right subcostal incision with a vertical midline extension. A ‘‘Mercedes’’ incision involved a bilateral subcostal incision with a vertical midline extension. The type of incision was determined by the location and size of HCC. Operative procedure. The hepatic resections that were performed were defined according to the Couinaud classification. Liver resections combined with vascular resection, diaphragmatic resection, or additional ablations were included. In principle, hepatic resection was performed with intermittent inflow occlusion, except for severe adhesion. This maneuver frequently is used in liver surgery to control bleeding when dividing the liver parenchyma by clamping the hepatoduodenal ligament and interrupting the flow of blood through the hepatic artery and the portal vein. The routine administration of prophylactic antibiotics was performed just before the operation and then usually continued for 48–72 hr after surgery. Method of abdominal wall closure. Closure of the abdominal wall muscle and fascia was performed in a single-layer mass closure with no. 1 absorbable monofilament Biosyn loops with a continuous running suture (Nippon Covidien Inc, Tokyo, Japan) or with no. 1 absorbable braid Vicryl interrupted sutures (Johnson & Johnson K. K., Tokyo, Japan). Skin closure was performed with subcuticular closure using a running 4-0 absorbable monofilament PDS suture (Johnson & Johnson K. K.) with a subcutaneous drainage tube. Diagnosis of IH. The definition of IH after hepatic resection has been previously described.13,14 IH was diagnosed on the basis of computed tomography (CT) findings. Generally, a hernia is defined as a protrusion that is covered with the peritoneum and protrudes from the abdominal wall. In this study, when fascial discontinuity of the abdominal wall was demonstrated by CT findings, the case was included in IH. A diagnosis of ‘‘no hernia’’ required a minimum followup of 12 months. Monitored perioperative factors. Preoperative factors included age, sex, BMI, diabetes mellitus, current smoking, Child–Pugh score, liver damage
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classification, number of platelets, indocyanine green retention test at 15 minutes (ICG15R), serum transferrin levels, serum prealbumin levels, serum P4NP 7S levels, and serum hyaluronic acid levels. Operative factors included repeat hepatectomy, duration of the operation, blood loss, intraoperative blood transfusion, type of incision, and method of abdominal wall closure. Postoperative factors included histopathologic status of the noncancerous part of the liver, SSI, and postoperative intractable ascites. Ascites was considered intractable when definitely observed by CT more than 1 month after surgery, despite diuretic administration. Statistical analysis. Data are expressed as the mean ± SD. Continuous variables were evaluated using the Student t test or the Wilcoxon rank-sum test. Categorical data were compared using the v2 test or Fisher exact test. To identify the independent risk factors of IH, the factors that were significant with univariable analysis were subjected to multivariable analysis by the use of logistic regression analysis. Incidence rates for IH were calculated by means of the Kaplan–Meier method for estimating crude risk using the date of diagnosis of IH. All analyses were performed with the use of JMP Pro software (Version 11.0, SAS Institute Japan Ltd, Tokyo, Japan). RESULTS Patients’ characteristics and the incidence rate of IH. From April 2009 to March 2013, hepatic resection for HCC was performed in 251 consecutive patients with LC, and 192 (76.5%) of these patients met the inclusion criteria of this study. In 42 (21.9%) patients who died more than 12 months after surgery, evaluation of IH was performed at least once before death. The median length of follow-up for IH was 27 months (range, 1–64 months). Of these 192 patients, 116 (60.4%) had hepatitis C virus infection, 35 (18.2%) had hepatitis B virus infection, 1 (0.5%) had both hepatitis C and B virus infections, and 40 (20.8%) had no infection. A total of 167 (87.0%) patients received open abdominal surgery, and 25 (13.0%) had laparoscopic-assisted surgery. A total of 152 (79.2%) patients had a J-shaped incision, 19 (9.9%) had a median incision, 14 (7.3%) had a right subcostal incision, and 7 (3.6%) had a ‘‘Mercedes’’ incision. In total, IH occurred in 60 (31.3%) patients. Among these 60 patients, the site of hernias was the lateral area in 33 (55.0%), the trifurcation area in 15 (25.0%), the median area in 9 (15.0%), and all 3 areas in 3 (5.0%) patients. The Kaplan–Meier estimated incidence rates of IH
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Fig 1. Kaplan–Meier analysis of the rate of IH after hepatic resection for HCC in patients with LC. Incidence rates for IH were calculated by the Kaplan–Meier method for estimating crude risk using the date of diagnosis of IH. The estimated incidence rates of IH were 19.8% at 12 months, 28.7% at 24 months, 32.5% at 36 months, 34.0% at 48 months, and 38.8% at 60 months.
were 19.8% at 12 months, 28.7% at 24 months, 32.5% at 36 months, 34.0% at 48 months, and 38.8% at 60 months (Fig 1). Univariable analysis. Table I shows univariable analysis of the association of risk factors with development of IH. Among 22 possible risk factors (including 13 preoperative, 6 intraoperative and 3 postoperative factors), 12 of these were significant as follows: BMI (P = .0058), Child–Pugh score (P = .0078), liver damage classification (P = .0247), number of platelets (P = .0021), ICG15R (P = .0046), serum P4NP 7S levels (P = .0006), serum hyaluronic acid levels (P = .0299), intraoperative blood transfusion (P = .0124), method of abdominal wall closure (P = .0388), histopathologic status of the noncancerous part of the liver (P = .0019), SSI (P = .0124), and postoperative intractable ascites (P < .0001). Multivariable analysis. To identify the independent risk factors of IH, the 12 factors that were significant in univariable analysis were subjected to multivariable analysis using logistic regression analysis. Continuous variables were divided into two groups using the cutoff point calculated by a receiver operating characteristic (ROC) curve (Fig 2). Four independent risk factors for IH were identified (Table II), including the presence of postoperative intractable ascites (odds ratio 24.83, P = .0003), abdominal wall closure by a singlelayer mass closure with a continuous running suture (odds ratio 4.59, P = .0143), preoperative BMI $25 kg/m2 (odds ratio 3.36, P = .0025), and
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Table I. Univariable analysis of risk factors for IH after hepatic resection for hepatocellular carcinoma in patients with LC Variables Preoperative factors Age Sex, male/female DM, yes/no Current smoking, yes/no BMI, kg/m2 Child-Pugh score, 5/6 and 7 Liver damage classification, A/B Platelets, 104/mL ICG15R, % P4NP 7S, ng/mL Hyaluronic acid, ng/mL Transferrin, mg/dL Prealbumin, mg/dL Intraoperative factors Repeat hepatectomy, yes/no Duration of operation, min Blood loss, mL Blood transfusion, yes/no Incision type, J-shaped/median/subcostal/Mercedes Abdominal wall closure, continuous/intermittent Postoperative factors Histopathologic status of noncancerous liver, LC/pre-LC SSI, yes/no Intractable ascites, yes/no
IH (+) group (n = 60)
IH ( ) group (n = 132)
P value
70.0 ± 7.3 41/19 17/43 10/50 24.4 ± 3.6 42/18 50/10 13.2 ± 7.8 22.9 ± 11.3 7.2 ± 6.4 244.3 ± 279.6 265.9 ± 61.2 18.4 ± 6.6
69.7 ± 9.3 92/40 54/78 31/101 23.0 ± 3.0 117/15 124/8 15.6 ± 6.8 18.5 ± 10.7 5.6 ± 1.7 181.6 ± 258.2 268.6 ± 54.1 19.7 ± 6.6
.8069 .8497 .0905 .2898 .0058 .0078 .0247 .0021 .0046 .0006 .0299 .7602 .1987
18/42 255.9 ± 100.0 531.4 ± 585.7 15/45 101/16/11/4 55/4*
53/79 244.4 ± 92.2 406.4 ± 558.0 14/118 51/3/3/3 109/23
.1730 .4364 .1685 .0124 .2776 .0388
39/21 15/45 10/50
54/78 14/118 1/131
.0019 .0124 <.001
*One operative record did not describe the method of abdominal closure. BMI, Body mass index; DM, diabetes mellitus; ICG15R, indocyanine green retention test at 15 minutes; IH, incisional hernia; LC, liver cirrhosis; P4NP 7S, N-terminal pro-peptide of type IV collagen 7S domain; SSI, surgical-site infection.
preoperative serum P4NP 7S levels $5 ng/mL (odds ratio 3.13, P = .0234). DISCUSSION IH is one of the most common complications after abdominal surgery. As many as 80–95% of patients with IH develop this complication within 6–36 months after the initial operation.4 Indeed, in our study, the rates of the incidence of IH increased progressively until 36 months postoperatively and then generally continued to plateau. Prevention of development of IH is important to avoid suffering in patients and to reduce medical treatment costs for the welfare system. Liver resection sometimes requires a wide incision be made. Many patients who undergo hepatectomy are concerned about wound complications, especially IH. In our study, there were no significant differences in incision type, repeat hepatectomy, age, and sex between the IH (+) and IH ( ) groups. This study included only HCC patients with LC because conditions of the liver are different between patients with HCC
versus LM. Generally, patients with HCC have severe liver dysfunction with various degrees of liver fibrosis due to LC. Liver fibrosis is diagnosed by histologic analysis of liver biopsy specimens. However, liver biopsy is invasive and is limited by sampling errors, diagnostic inaccuracy, and hazards to the patient. Therefore, to assess the degree of liver fibrosis, alternative noninvasive serum markers, including transferrin, P4NP 7S, and hyaluronic acid, are tested preoperatively.15,20 Type IV collagen is the most important structural component of the basement membrane, which constitutes one part of the extracellular matrix. P4NP is known to self-assemble into a polymer and has a network-like structure consisting of a 7S domain complex with helix regions. This structure is only soluble and unmasked after digestion by pepsin in a healthy state. After pepsin pretreatment of type IV collagen, it becomes soluble and available (eg, gelatinase cleavage). When the liver becomes fibrotic, stellate cells and lipocytes start to deposit basement membrane proteins, such as laminin and type IV collagen, around
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Fig 2. ROC curves for the development of IH after hepatic resection for HCC in patients with LC. The optimal cutoff thresholds of BMI, serum P4NP 7S levels, ICG15R, number of platelets, and serum hyaluronic acid levels were calculated by ROC curve. (A) BMI. The area under the ROC curve (AUC) was 0.6244. The optimal cutoff threshold was 25 kg/m2. (B) P4NP 7S levels. The AUC was 0.6551. The optimal cutoff threshold was 5 ng/mL. (C) ICG15R. The AUC was 0.6278. The optimal cutoff threshold was 15%. (D) Number of platelets. The AUC was 0.6386. The optimal cutoff threshold was 14 3 104/mL. (E) Serum hyaluronic acid levels. The AUC was 0.5981. The optimal cutoff threshold was 120 ng/mL.
Table II. Multivariable analysis of risk factors for IH after hepatic resection for hepatocellular carcinoma in patients with LC Variable
Parameter
Odds ratio
95% CI
P value
Intractable ascites BMI, kg/m2 Abdominal wall closure P4NP 7S, ng/mL ICG15R, % Child-Pugh score Platelets, 104/mL SSI Histopathologic status of noncancerous liver Liver damage classification Blood transfusion Hyaluronic acid, ng/mL
Yes $25 Continuous $5 $15 6 and 7 <14 Yes LC B Yes $120
24.83 3.36 4.59 3.13 2.09 2.48 1.31 1.36 0.86 0.92 1.03 1.00
3.78–500.93 1.53–7.59 1.33–20.77 1.16–9.12 0.89–5.09 0.81–7.77 0.57–3.03 0.49–3.67 0.35–2.06 0.23–3.69 0.36–2.85 0.42–2.38
.0003 .0025 .0143 .0234 .0889 .1126 .5282 .5431 .7418 .9225 .9568 .9987
BMI, Body mass index; CI, confidence interval; ICG15R, indocyanine green retention test at 15 minutes; IH, incisional hernia; LC, liver cirrhosis; P4NP 7S, N-terminal pro-peptide of type IV collagen 7S domain; SSI, surgical-site infection.
the subendothelial sinusoids and in the space of Disse, which contributes to impaired hepatocellular function. Therefore, P4NP 7S is a potential biochemical marker for basement
membrane turnover during liver fibrosis and reflects the abnormality of type IV collagen.21 Collagen metabolism in patients with a hernia is altered at 3 levels: the type I/III collagen ratio is
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decreased, the quality of collagen is poorer, and collagen breakdown is increased.22 Studies on skin and fascia samples from patients with IH have shown a significantly decreased ratio of type I/III collagen and type I/III procollagen mRNA compared with controls.23-27 This lower ratio is caused by an increase in the amount of type III collagen in patients with IH. Furthermore, some of these reports have described that patients with IH have systemically altered type IV collagen metabolism. Salameh et al25 reported that type V collagen is not altered, whereas type IV collagen appears to be undetectable in fascia of patients with IH. Another study reported that overexpression of the gene coding for collagen type IV is found in the skin of patients with recurrent IH.26 Recently, Henriksen et al27 reported that synthesis of type IV collagen was increased in patients with IH and the best model for predicting the presence of hernias included the turnover of type IV collagen. These results suggest that, even though a hernia presents as a local phenomenon, formation of a hernia is a systemic disease, and a systemically altered quality of type IV collagen may lead to a greater risk of formation of hernias. In our study, preoperative serum P4NP 7S levels $5 ng/ mL were an independent risk factor for IH. This result suggests that abnormality of type IV collagen might be not only a consequence of liver fibrosis but also the cause of IH. Risk factors can be divided into patient- and surgeon-related factors. Although patient-related factors cannot be controlled, surgeon-related factors (eg, the choice of suture material, the method of abdominal wall closure, and the quality of the suture technique) can be controlled entirely by the surgeon. Our study showed that abdominal wall closure by a single-layer mass closure with a continuous running suture was an independent risk factor for IH. One of the reasons for this finding might be that no. 1 absorbable monofilament Biosyn loops, the suture material used in this study, does not have sufficient tensile strength retention. Generally, a normally healed wound has gained 50% of its original strength after approximately 6 weeks.28 According to the product document, the breaking strength retention after 3 weeks of no. 1 absorbable monofilament Biosyn loops is approximately 40%, and this suture material is almost completely absorbed after approximately 90–110 days. Other suture material with a more powerful and prolonged tensile strength retention should be used. In conclusion, although there are several risk factors for IH after hepatic resection in HCC
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patients with LC, preoperative serum P4NP 7S levels $5 ng/mL are a useful predictive marker for the development of IH, and abdominal wall closure with a continuous running suture by a single-layer mass closure should be avoided to prevent IH. REFERENCES 1. Nicolle LE, Huchcroft SA, Cruse PJ. Risk factors for surgical wound infection among elderly. J Clin Epidemiol 1992;45: 357-64. 2. Llaguna OH, Avgerinos DV, Lugo JZ, Matatov T, Abbadessa B, Martz JE, et al. Incidence and risk factors for the development of incisional hernia following elective laparoscopic versus open colon resections. Am J Surg 2010;200:265-9. 3. Bucknall TE, Cox PJ, Ellis H. Burst abdomen and incisional hernia: a prospective study of 1129 major laparotomies. Br Med J (Clin Res Ed) 1982;284:931-3. 4. Mudge M, Hughes LE. Incisional hernia: a 10 year prospective study of incidence and attitudes. Br J Surg 1985;72:70-1. 5. Veljkovic R, Protic M, Gluhovic A, Potic Z, Milosevic Z, Stojadinovic A. Prospective clinical trial of factors predicting the early development of incisional hernia after midline laparotomy. J Am Coll Surg 2010;210:210-9. 6. Laurent C, Leblanc F, Bretagnol F, Capdepont M, Rullier E. Long-term wound advantages of the laparoscopic approach in rectal cancer. Br J Surg 2008;95:903-8. 7. Gruppo M, Mazzalai F, Lorenzetti R, Piatto G, Toniato A, Ballotta E. Midline abdominal wall incisional hernia after aortic reconstructive surgery: a prospective study. Surgery 2012;151:882-8. 8. Seilar CM, Deckert A, Diener MK, Knaebel HP, Weigand MA, Victor N, et al. Midline versus transverse incision in major abdominal surgery: a randomized, doubleblind equivalence trial (POVATI: ISRCTN60734227). Ann Surg 2009;249:913-20. 9. Taylor GW, Jayne DG, Brown SR, Thorpe H, Brown JM, Dewberry SC, et al. Adhesions and incisional hernias following laparoscopic versus open surgery for colorectal cancer in the CLASICC trial. Br J Surg 2010;97:70-8. 10. Itatsu K, Yokoyama Y, Sugawara G, Kubota H, Tojima Y, Kurumiya Y, et al. Incidence of and risk factors for incisional hernia after abdominal surgery. Br J Surg 2014;101:1439-47. 11. Diener MK, Voss S, Jensen K, Buchler MW, Seiler CM. Elective midline laparotomy closure: the INLINE systematic review and meta- analysis. Ann Surg 2010;251:843-56. 12. Burger JW, Luijendijk RW, Hop WC, Halm JA, Verdaasdonk EG, Jeekel J. Long-term follow-up of a randomized controlled trial of suture versus mesh repair of incisional hernia. Ann Surg 2004;240:578-85. 13. Togo S, Nagano Y, Matsumoto C, Takakura H, Matsuo K, Takeda K, et al. Outcome of and risk factors for incisional hernia after partial hepatectomy. J Gastrointest Surg 2008; 12:1115-20. 14. D’Angelica M, Maddineni S, Fong Y, Martin RC, Cohen MS, Ben-Porat L, et al. Optimal abdominal incision for partial hepatectomy: increased late complications with Mercedestype incisions compared to extended right subcostal incisions. World J Surg 2006;30:410-8. 15. Soresi M, Giannitrapani L, Cervello M, Licata A, Montalto G. Non invasive tools for the diagnosis of liver cirrhosis. World J Gastroenterol 2014;20:18131-50. 16. Kalaitzakis E. Gastrointestinal dysfunction in liver cirrhosis. World J Gastroenterol 2014;20:14686-95.
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17. Hanai T, Shiraki M, Nishimura K, Ohnishi S, Imai K, Suetsugu A, et al. Sarcopenia impairs prognosis of patients with liver cirrhosis. Nutrition 2015;31:193-9. 18. Bonnel AR, Bunchorntavakul C, Reddy KR. Immune dysfunction and infection in patients with cirrhosis. Clin Gastroenterol Hepatol 2011;9:727-38. 19. Garcia-Tsao G, Friedman S, Iredale J, Pinzani M. Now there are many (stages) where before there was one: In search of a pathophysiological classification of cirrhosis. Hepatology 2010;51:1445-9. 20. Cho HJ, Kim SS, Ahn SJ, Park JH, Kim DJ, Kim YB, et al. Serum transferrin as a liver fibrosis biomarker in patients with chronic hepatitis B. Clin Mol Hepatol 2014;20:347-54. 21. Leeming DJ, Nielsen MJ, Dai Y, Veidal SS, Vassiliadis E, Zhang C, et al. Enzyme-linked immunosorbent serum assay specific for the 7S domain of Collagen Type IV (P4NP 7S): A marker related to the extracellular matrix remodeling during liver fibrogenesis. Hepatol Res 2012;42:482-93. 22. Henriksen NA, Yadete DH, Srensen LT, Agren MS, Jogensen LN. Connective tissue alternation in abdominal wall hernia. Br J Surg 2011;98:210-9.
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23. Si Z, Bhardwaj R, Rosch R, Mertens PR, Klosterhalfen B, Klinge U. Impaired balance of type I and type III procollagen mRNA in cultured fibroblasts of patients with incisional hernia. Surgery 2002;131:324-31. 24. White B, Osier C, Gletsu N, Jeansonne L, Baghai M, Sherman M, et al. Abnormal primary tissue collagen composition in the skin of recurrent incisional hernia patients. Am Surg 2007;73:1254-8. 25. Salameh JR, Talbott LM, May W, Gosheh B, Vig PJ, McDaniel DO. Role of biomarkers in incisional hernias. Am Surg 2007;73:561-8. 26. Galaluce R, Davis JW, Bachman SL, Gubin MM, Brown JA, Magee JD, et al. Incisional hernia recurrence through genomic profiling: a pilot study. Hernia 2013;17:193-202. 27. Henriksen NA, Mortensen JH, Sorensen LT, Bay-Jensen AC, Agren MS, Jorgensen LN, et al. The collagen turnover profile is altered in patients with inguinal and incisional hernia. Surgery 2015;157:312-21. 28. Israelsson LA, Millbourn D. Prevention of incisional hernias: how to close a midline incision. Surg Clin North Am 2013;93:1027-40.