Prospective Study of Perioperative Circulating Tumor DNA Dynamics in Patients Undergoing Hepatectomy for Colorectal Liver Metastases.

OBJECTIVE: To evaluate the association of perioperative ctDNA dynamics on outcomes after hepatectomy for CLM. SUMMARY BACKGROUND DATA: Prognostication is imprecise for patients undergoing hepatectomy for CLM, and ctDNA is a promising biomarker. However, clinical implications of perioperative ctDNA dynamics are not well established. METHODS: Patients underwent curative-intent hepatectomy after preoperative chemotherapy for CLM (2013-2017) with paired prehepatectomy/postoperative ctDNA analyses via plasma-only assay. Positivity was determined using a proprietary variant classifier. Primary endpoint was recurrence-free survival (RFS). Median follow-up was 55 months. RESULTS: Forty-eight patients were included. ctDNA was detected before and after surgery (ctDNA+/+) in 14 (29%), before but not after surgery (ctDNA+/-) in 19 (40%), and not at all (ctDNA-/-) in 11 (23%). Adverse tissue somatic mutations were detected in TP53 (n = 26; 54%), RAS (n = 23; 48%), SMAD4 (n = 5; 10%), FBXW7 (n = 3; 6%), and BRAF (n = 2; 4%). ctDNA+/+ was associated with worse RFS (median: ctDNA+/+, 6.0 months; ctDNA+/-, not reached; ctDNA-/-, 33.0 months; P = 0.001). Compared to ctDNA+/+, ctDNA+/- was associated with improved RFS [hazard ratio (HR) 0.24 (95% confidence interval (CI) 0.1-0.58)] and overall survival [HR 0.24 (95% CI 0.08-0.74)]. Adverse somatic mutations were not associated with survival. After adjustment for prehepatectomy chemotherapy, synchronous disease, and ≥2 CLM, ctDNA+/- and ctDNA-/- were independently associated with improved RFS compared to ctDNA+/+ (ctDNA+/-: HR 0.21, 95% CI 0.08-0.53; ctDNA-/-: HR 0.21, 95% CI 0.08-0.56). CONCLUSIONS: Perioperative ctDNA dynamics are associated with survival, identify patients with high recurrence risk, and may be used to guide treatment decisions and surveillance after hepatectomy for patients with CLM.

The prognostic impact of RAS on overall survival following liver resection in early versus late-onset colorectal cancer patients.

BACKGROUND: The impact of molecular aberrations on survival after resection of colorectal liver metastases (CLM) in patients with early-age-onset (EOCRC) versus late-age-onset colorectal cancer (LOCRC) is unknown. METHODS: Patients who underwent liver resection for CLM with known RAS, BRAF and MSI status were retrospectively studied. The prognostic impact of RAS mutations by age was analysed with age as a categorical variable and a continuous variable. RESULTS: The study included 573 patients, 192 with EOCRC and 381 with LOCRC. The younger the age of onset of CRC, the greater the negative impact on overall survival of RAS mutations in the LOCRC, EOCRC, and ≤40 years (hazard ratio (HR), 1.64 (95% confidence interval (CI), 1.23-2.20), 2.03 (95% CI, 1.30-3.17), and 2.97 (95% CI, 1.44-6.14), respectively. Age-specific mortality risk and linear regression analysis also demonstrated that RAS mutations had a greater impact on survival in EOCRC than in LOCRC (slope: -4.07, 95% CI -8.10 to 0.04, P = 0.047, R2 = 0.08). CONCLUSION: Among patients undergoing CLM resection, RAS mutations have a greater negative influence on survival in patients with EOCRC, more so in patients ≤40 years, than in patients with LOCRC and should be considered as a prognostic factor in multidisciplinary treatment planning.

Comprehensive Complication Index Validates Improved Outcomes Over Time Despite Increased Complexity in 3707 Consecutive Hepatectomies.

OBJECTIVE: The aim of this study was to evaluate trends over time in perioperative outcomes for patients undergoing hepatectomy. BACKGROUND: As perioperative care and surgical technique for hepatectomy have improved, the indications for and complexity of liver resections have evolved. However, the resulting effect on the short-term outcomes over time has not been well described. METHODS: Consecutive patients undergoing hepatectomy during 1998 to 2015 at 1 institution were analyzed. Perioperative outcomes, including the comprehensive complication index (CCI), were compared between patients who underwent hepatectomy in the eras 1998 to 2003, 2004 to 2009, and 2010 to 2015. RESULTS: The study included 3707 hepatic resections. The number of hepatectomies increased in each era (794 in 1998 to 2003, 1402 in 2004 to 2009, and 1511 in 2010 to 2015). Technical complexity increased over time as evidenced by increases in the rates of major hepatectomy (20%, 23%, 30%, P < 0.0001), 2-stage hepatectomy (0%, 3%, 4%, P < 0.001), need for portal vein embolization (5%, 9%, 9%, P = 0.001), preoperative chemotherapy for colorectal liver metastases (70%, 82%, 89%, P < 0.001) and median operative time (180, 175, 225 minutes, P < 0.001). Significant decreases over time were observed in median blood loss (300, 250, 200 mL, P < 0.001), transfusion rate (19%, 15%, 5%, P < 0.001), median length of hospitalization (7, 7, 6 days, P < 0.001), rates of CCI ≥26.2 (20%, 22%, 16%, P < 0.001) and 90-day mortality (3.1%, 2.6%, 1.3%, P < 0.01). On multivariable analysis, hepatectomy in the most recent era 2010 to 2015 was associated with a lower incidence of CCI ≥26.2 (odds ratio 0.7, 95% confidence interval 0.6-0.8, P < 0.0001). CONCLUSION: Despite increases in complexity over an 18-year period, continued improvements in surgical technique and perioperative outcomes yielded a resultant decrease in CCI in the most current era.

Optimal future liver remnant in patients treated with extensive preoperative chemotherapy for colorectal liver metastases.

BACKGROUND: Patients with colorectal liver metastases (CLM) are increasingly treated with preoperative chemotherapy. Chemotherapy associated liver injury is associated with postoperative hepatic insufficiency (PHI) and mortality. The adequate minimum future liver remnant (FLR) volume in patients treated with extensive chemotherapy remains unknown. METHODS: All patients with standardized FLR > 20 %, who underwent extended right hepatectomy for CLM from 1993-2011, were divided into three cohorts by chemotherapy duration: no chemotherapy (NC, n = 30), short duration (SD, ≤12 weeks, n = 78), long duration (LD, >12 weeks, n = 86). PHI and mortality were compared by using uni-/multivariate analyses. Optimal FLR for LD chemotherapy was determined using a minimum p-value approach. RESULTS: A total of 194 patients met inclusion criteria. LD chemotherapy was significantly associated with PHI (NC + SD 3.7 vs. LD 16.3%, p = 0.006). Ninety-day mortality rates were 0 % in NC, 1.3 % in SD, and 2.3% in LD patients, respectively (p = 0.95). In patients with FLR > 30 %, PHI occurred in only two patients (both LD, 2/20, 10 %), but all patients with FLR > 30 % survived. The best cutoff of FLR for preventing PHI after chemotherapy >12 weeks was estimated as >30 %. Both LD chemotherapy (odds ratio [OR] 5.4, p = 0.004) and FLR ≤ 30 % (OR 6.3, p = 0.019) were independent predictors of PHI. CONCLUSIONS: Preoperative chemotherapy >12 weeks increases the risk of PHI after extended right hepatectomy. In patients treated with long-duration chemotherapy, FLR > 30 % reduces the rate of PHI and may provide enough functional reserve for clinical rescue if PHI develops.

Is This Patient's Liver Mass Cancer?

Undiagnosed liver lesions are important findings that can affect the physical and mental well-being of patients. They are usually incidental findings identified while clinicians are performing other imaging tests. It is important for clinicians and patients to identify the causative factors for these lesions in order to further reduce risk, develop treatment plans, and produce better outcomes. Both men and women can develop liver lesions, which may require surgical intervention. Knowing the key risk factors for common lesions can help clinicians confidently diagnose patients without costly workup.

Interactions of multiple gene alterations in colorectal liver metastases.

The advancements in next generation sequencing have expanded the information available in clinical practice. Alterations of TP53, APC, RAS, PIK3CA, and SMAD4 are present in more than 10% of patients with colorectal liver metastases (CLM). Of these genes, TP53, RAS and SMAD4 were associated with worse survival in patients undergoing CLM resection. Testing multiple gene alterations provides a more precise prognosis for patients undergoing CLM resection and may be useful for better clinical decision making.

Advanced Practitioners: Collaborators in Radiation Oncology.

Advanced practitioners (APs), including physician assistants (PAs) and nurse practitioners (NPs), are medical professionals with advanced training, degrees, and certifications that qualify them to diagnose and treat medical conditions in a wide variety of health-care settings. As such, APs have been collaborators in radiation oncology practice for decades to complement the role of radiation oncologists. In 1999, Kelvin and Moore-Higgs first reported data on how APs participated in radiation oncology practice. Over the 20 years since that publication, more articles have described how APs have been collaborators to varying degrees in nearly all aspects of radiation oncology practice. However, significant legislative, regulatory, and educational barriers may limit the optimal practice of APs in radiation oncology. In order to mitigate projected shortages of radiation oncology services while maintaining high levels of patient satisfaction, enhanced collaboration with APs in radiation oncology practice is needed.

Comparison of two methods of future liver remnant volume measurement.

BACKGROUND: In liver transplantation, a minimum graft to patient body weight (BW) ratio is required for graft survival; in liver resection, total liver volume (TLV) calculated from body surface area (BSA) is used to determine the future liver remnant (FLR) volume needed for safe hepatic resection. These two methods of estimating liver volume have not previously been compared. The purpose of this study was to compare FLR volumes standardized to BW versus BSA and to assess their utility in predicting postoperative hepatic dysfunction after hepatic resection. METHODS: Records were reviewed of 68 consecutive noncirrhotic patients who underwent major hepatectomy after portal vein embolization between 1998 and 2006. FLR (cubic centimeter) was measured preoperatively with three-dimensional helical computed tomography; TLV (cubic centimeter) was calculated from the patients' BSA. The relationship between FLR/TLV and FLR/BW (cubic centimeter per kilogram) was examined using linear regression analysis. Receiver operating characteristic (ROC) curve analysis was used to determine FLR/TLV and FLR/BW cutoff values for predicting postoperative hepatic dysfunction (defined as peak bilirubin level>3 mg/dl or prothrombin time>18 s). RESULTS: Regression analysis revealed that the FLR/TLV and FLR/BW ratios were highly correlated (Pearson correlation coefficient, 0.98). The area under the ROC curve was 0.85 for FLR/TLV and 0.84 for FLR/BW (95% confidence interval, 0.71-0.97). Sixteen of the 68 patients developed postoperative hepatic dysfunction. The ROC curve analysis yielded a cutoff FLR/BW value of

Two-Stage Hepatectomy vs One-Stage Major Hepatectomy with Contralateral Resection or Ablation for Advanced Bilobar Colorectal Liver Metastases.

BACKGROUND: Both 2-stage hepatectomy (TSH) and 1-stage hepatectomy (OSH) represent feasible strategies for resection of advanced bilobar colorectal liver metastases (CLM). However, the influence of the surgical approach on postoperative outcomes and overall survival (OS) is unknown. To define the optimal surgical approach for advanced bilobar CLM requiring right hemihepatectomy, we compared short-term and long-term outcomes after TSH and OSH with contralateral resection or radiofrequency ablation (RFA). STUDY DESIGN: We retrospectively reviewed 227 patients with bilobar CLM, who underwent right or extended right hepatectomy with treatment of synchronous CLM in segments I, II, and/or III, between 1998 and 2015. Postoperative outcomes and OS were compared between patients who underwent TSH and those who underwent OSH. RESULTS: Of the 227 patients, 126 (56%) underwent at least the first stage of TSH, and 101 (44%) underwent OSH, 29 (13%) without RFA and 72 (32%) with RFA. Two-stage hepatectomy was associated with a lower incidence of postoperative major complications (14% vs 26%, p = 0.03) and postoperative hepatic insufficiency (6% vs 20%, p = 0.001) than OSH. The 5-year OS rate was higher for patients assigned to TSH than for those who underwent OSH (35% vs 24%, p = 0.016). Patients who completed both stages of TSH had a higher 5-year OS rate than patients who underwent OSH without RFA (50% vs 20%, p = 0.023) or OSH with RFA (50% vs 24%, p < 0.0001). CONCLUSIONS: In patients with advanced bilobar CLM, TSH is associated with fewer complications than OSH. Both TSH in intention-to-treat analysis and completed TSH in as-treated analysis were associated with better OS than OSH.

SMAD4 gene mutation predicts poor prognosis in patients undergoing resection for colorectal liver metastases.

INTRODUCTION: Dorsophilia protein, mothers against decapentaplegic homolog 4 (SMAD4) is a key mediator in the transforming growth factor (TGF)-ß signaling pathway and SMAD4 gene mutations are thought to play a critical role in colorectal cancer (CRC) progression. However, little is known about its influence on survival in patients undergoing resection for colorectal liver metastases (CLM). METHODS: Between 2005 and 2015, all patients with known SMAD4 mutation status who underwent resection of CLM were identified. Patients with SMAD4 mutation were compared to those with SMAD4 wild type. Next, the prognostic value of SMAD4 mutation was validated in a separate cohort of patients with synchronous stage IV CRC who underwent systemic therapy alone. RESULTS: Of 278 patients, 37 (13%) were SMAD4 mutant while 241 (87%) were wild type. Overall survival (OS) after hepatic resection was worse in SMAD4-mutant patients compared to SMAD4 wild type (OS rate at 3 years, 62% vs. 82%; P < 0.0001). Independent predictors for worse OS were poor differentiation (hazard ratio [HR] 2.586; P = 0.007), multiple tumors (HR 1.970; P = 0.01), diameter greater than 3 cm (HR 1.752; P = 0.017), R1 margin status (HR 2.452; P = 0.014), RAS mutation (HR 2.044; P = 0.002), and SMAD4 mutation (HR 2.773; P < 0.0001). Among 237 patients in the validation cohort, SMAD4-mutations were significantly associated with worse 3-year OS rate (22% vs. 38%; P = 0.012) and was an independent predictor for worse OS (HR, 1.647; P = 0.032). CONCLUSION: SMAD4 mutation is independently associated with worse outcomes among patients undergoing resection of CLM.

Systemic chemotherapy and two-stage hepatectomy for extensive bilateral colorectal liver metastases: perioperative safety and survival.

BACKGROUND: Two-stage hepatectomy has been proposed for patients with bilateral colorectal liver metastases (CLM). The aim of this study was to compare the outcome of patients with CLM treated with preoperative chemotherapy followed by one- or two-stage hepatectomy. METHODS: From a prospective database, 214 consecutive patients who received preoperative systemic chemotherapy (fluoropyrimidine with irinotecan or oxaliplatin) followed by planned one- or two-stage hepatectomy were retrospectively analyzed (1998-2006). In patients undergoing two-stage procedures, minor hepatectomy (wedge or segmental resection[s]) was systematically performed before major (more than three segments), second-stage hepatectomy. Preoperative portal vein embolization (PVE) was performed if indicated. RESULTS: One- (group I) and two-stage (group II) hepatectomies were performed in 184 and 21 patients, respectively. Median number of metastases in groups I and II were two (range 1-20) and seven (range 2-20). All patients in group II had bilateral disease vs 39% in group I. Major hepatectomy was performed in all patients in group II and 79% in group I. PVE was performed in 18 group I and 12 group II patients without increase in morbidity. For group I, group II first stage, and group II second stage, respectively, morbidity (24%, 24%, 43%), median hospital stay (7 days, 6 days, 6.5 days) and 30 days postoperative mortality (2%, 0%, 0%) were not significantly different (P = NS). Median follow-up was 25 months; median survival has not been reached. One- and 3-year overall and disease-free survival rates from the time of hepatic resection were 95% and 75%, 63% and 39%, respectively in group I; 95% and 86%, 70% and 51%, respectively in group II (P = NS). CONCLUSIONS: Two-stage hepatectomy with preoperative chemotherapy results in comparable morbidity and survival rates as one-stage hepatectomy. This approach enables selection and treatment of patients with multiple, bilateral CLM who will benefit from aggressive surgery with good outcomes.

RAS Mutation Is Associated with Decreased Survival in Patients Undergoing Repeat Hepatectomy for Colorectal Liver Metastases.

BACKGROUND: The relationship between RAS mutation status and outcome for patients undergoing repeat hepatectomy (RH) for recurrent colorectal liver metastases (CLM) has not been defined. OBJECTIVE: The objective of this study was to evaluate the relationship between RAS mutation status and outcome in patients undergoing RH for CLM. METHODS: All patients who underwent RH for CLM with known RAS mutation status between January 2005 and November 2014 were identified, and the outcomes of patients with and without RAS mutations were compared. RESULTS: Ninety-eight patients underwent RH, of whom 34 (35 %) harbored a RAS mutation. Wild-type (WT) and mutant RAS groups had similar clinicopathologic characteristics. Median recurrence-free survival (RFS) for patients with WT and mutant RAS was 12.2 and 6.1 months, respectively (p = 0.03). Median overall survival (OS) for the WT and mutant RAS patients were 42.5 and 26.6 months, respectively (p < 0.01). On multivariate analysis, RAS mutations [hazard ratio (HR) = 1.69, p = 0.04] were associated with worse RFS, while multiple tumors (HR = 1.92, p = 0.045) and RAS mutations (HR = 2.11, p = 0.02) predicted worse OS. CONCLUSION: Patients with recurrent CLM that harbor RAS mutations have worse RFS and OS than patients with WT RAS, and RAS mutations are independently associated with worse RFS and OS. RAS mutation status should be determined prior to RH, as it may impact treatment decisions.

Solitary colorectal liver metastasis: resection determines outcome.

BACKGROUND: Hepatic resection (HR) and radiofrequency ablation (RFA) have been proposed as equivalent treatments for colorectal liver metastasis. HYPOTHESIS: Recurrence patterns after HR and RFA for solitary liver metastasis are similar. DESIGN: Analysis of a prospective database at a tertiary care center with systematic review of follow-up imaging in all of the patients. PATIENTS AND METHODS: Patients with solitary liver metastasis as the first site of metastasis treated for cure by HR or RFA were studied (patients received no prior liver-directed therapy). Prognostic factors, recurrence patterns, and survival rates were analyzed. RESULTS: Of the 180 patients who were studied, 150 underwent HR and 30 underwent RFA. Radiofrequency ablation was used when resection would leave an inadequate liver remnant (20 patients) or comorbidity precluded safe HR (10 patients). Tumor size and treatment determined recurrence and survival. The local recurrence (LR) rate was markedly lower after HR (5%) than after RFA (37%) (P<.001). Treatment by HR was associated with longer 5-year survival rates than RFA, including LR-free (92% vs 60%, respectively; P<.001), disease-free (50% vs 0%, respectively; P = .001), and overall (71% vs 27%, respectively; P<.001) survival rates. In the subset with tumors 3 cm or larger (n = 79), LR occurred more frequently following RFA (31%) than after HR (3%) (P = .001), with a 5-year LR-free survival rate of 66% after RFA vs 97% after HR (P<.001). Patients with small tumors experienced longer 5-year overall survival rates after HR (72%) as compared with RFA (18%) (P = .006). CONCLUSIONS: The survival rate following HR of solitary colorectal liver metastasis exceeds 70% at 5 years. Radiofrequency ablation for solitary metastasis is associated with a markedly higher LR rate and shorter recurrence-free and overall survival rates compared with HR, even when small lesions (< or = 3 cm) are considered. Every method should be considered to achieve resection of solitary colorectal liver metastasis, including referral to a specialty center, extended hepatectomy, and chemotherapy.

Improved long-term survival after major resection for hepatocellular carcinoma: a multicenter analysis based on a new definition of major hepatectomy.

BACKGROUND: Advances in the surgical management of hepatocellular carcinoma (HCC) have expanded the indications for curative hepatectomy, including more extensive liver resections. The purpose of this study was to examine long-term survival trends for patients treated with major hepatectomy for HCC. PATIENTS AND METHODS: Clinicopathologic data for 1,115 patients with HCC who underwent hepatectomy between 1981 and 2008 at five hepatobiliary centers in France, China, and the USA were assessed. In addition to other performance metrics, outcomes were evaluated using resection of ≥4 liver segments as a novel definition of major hepatectomy. RESULTS: Major hepatectomy was performed in 539 patients. In the major hepatectomy group, median tumor size was 10 cm (range: 1-27 cm) and 22 % of the patients had bilateral lesions. The TNM Stage distribution included 29 % Stage I, 31 % Stage II, 38 % Stage III, and 2 % Stage IV. The postoperative histologic examination indicated that chronic liver disease was present in 35 % of the patients and tumor microvascular invasion was identified in 60 % of the patients. The 90-day postoperative mortality rate was 4 %. After a median follow-up time of 63 months, the 5-year overall survival rate was 40 %. Patients treated with right hepatectomy (n = 332) and those requiring extended hepatectomy (n = 207) had similar 90-day postoperative mortality rates (4 % and 4 %, respectively, p = 0.976) and 5-year overall survival rates (42 % and 36 %, respectively, p = 0.523). Postoperative mortality and overall survival rates after major hepatectomy were similar among the participating countries (p > 0.1) and improved over time with 5-year survival rates of 30 %, 40 %, and 51 % for the years 1981-1989, 1990-1999, and the most recent era of 2000-2008, respectively (p = 0.004). In multivariate analysis, factors that were significantly associated with worse survivals included AFP level >1,000 ng/mL, tumor size >5 cm, presence of major vascular invasion, presence of extrahepatic metastases, positive surgical margins, and earlier time period in which the major hepatectomy was performed. CONCLUSIONS: This multinational, long-term HCC survival analysis indicates that expansion of surgical indications to include major hepatectomy is justified by the significant improvement in outcomes over the past three decades observed in both the East and the West.

The association of family history of liver cancer with hepatocellular carcinoma: a case-control study in the United States.

BACKGROUND/AIMS: The study aimed at addressing the connection between positive family history of liver cancer and hepatocellular carcinoma (HCC) development in the USA. METHODS: At The University of Texas M.D. Anderson Cancer Center, 347 patients with pathologically confirmed HCC and 1075 healthy controls were studied. All subjects were interviewed for their family history of cancer, including the number of relatives with cancer, the type of cancer, the individual's relationship with the relative, and the age at which the relative was diagnosed. RESULTS: Independently of hepatitis B virus (HBV) and hepatitis C virus (HCV), a history of liver cancer in first degree relatives was significantly associated with HCC development (AOR=4.1 [95% CI, 1.3-12.9]). Multiple relatives with liver cancer were only observed among HCC patients with chronic HBV/HCV infection. Affected siblings with liver cancer is significantly associated with HCC development with and without HBV/HCV infection; (AOR=5.7 [95% CI, 1.2-27.3]) and (AOR=4.3 [95% CI, 1.01-20.9]), respectively. Individuals with HBV/HCV and a family history of liver cancer were at higher risk for HCC (AOR=61.9 [95% CI, 6.6-579.7]). CONCLUSIONS: First degree family history of liver cancer is associated with HCC development in the USA. Further research exploring the genetic-environment interactions associated with risk of HCC is warranted.

Is extended hepatectomy for hepatobiliary malignancy justified?

BACKGROUND: Extended hepatectomy may be required to provide the best chance for cure of hepatobiliary malignancies. However, the procedure may be associated with significant morbidity and mortality. METHODS: We analyzed the outcome of 127 consecutive patients who underwent extended hepatectomy (resection of > or = 5 liver segments) for hepatobiliary malignancies. RESULTS: The patients underwent extended hepatectomy for colorectal metastases (n = 86; 67.7%), hepatocellular carcinoma (n =12; 9.4%), cholangiocarcinoma (n =14; 11.0%), and other malignant diseases (n =15; 11.5%). Thirty-two left and ninety-five right extended hepatectomies were performed. Eight patients also underwent caudate lobe resection, and 40 patients underwent a synchronous intraabdominal procedure. Twenty patients underwent radiofrequency ablation, and 31 underwent preoperative portal vein embolization. The median blood loss was 300 mL for right hepatectomy and 600 mL for left hepatectomy (P = 0.02). Thirty-six patients (28.3%) received a blood transfusion. The overall complication rate was 30.7% (n = 39), and the operative mortality rate was 0.8% (n = 1). Significant liver insufficiency (total bilirubin level > 10 mg/dL or international normalized ratio > 2) occurred in 6 patients (4.7%). Multivariate analysis showed that a synchronous intraabdominal procedure was the only factor associated with an increased risk of morbidity (hazard ratio [HR], 4.9; P = 0.02). The median survival was 41.9 months. The overall 5-year survival rate was 25.5%. CONCLUSIONS: Extended hepatectomy can be performed with a near-zero operative mortality rate and is associated with long-term survival in a subset of patients with malignant hepatobiliary disease. Combining extended hepatectomy with another intraabdominal procedure increases the risk of postoperative morbidity.