Bleeding Recurrence and Mortality Following Interventional Management of Spontaneous HCC Rupture: Results of a Multicenter European Study.

BACKGROUND: The incidence of spontaneous rupture of hepatocellular carcinoma (HCC) is low in Europe, at less than 3%. HCC rupture remains a life-threatening complication, with mortality reported between 16 and 30%. The risk of bleeding recurrence has never been clearly evaluated in such clinical situation. The objectives of this study were to evaluate the current risk of mortality related to HCC rupture and to focus on the risk of bleeding recurrence following interventional management. METHODS: All patients admitted to 14 French-Italian surgical centers for spontaneous rupture of HCC between May 2000 and May 2012 were retrospectively included. Clinical data, imaging features, relevant laboratory data, treatment strategies, and prognoses were analyzed. RESULTS: Overall, 58 of the 138 included patients (42%) had cirrhosis. Thirty-five patients (25%) presented with hemorrhagic shock, and 19% with organ(s) dysfunction. Bleeding control was obtained by interventional hemostasis, emergency liver resection, and conservative medical management in 86 (62%), 24 (18%), and 21 (15%) patients, respectively. Best supportive care was chosen for 7 (5%) patients. The mortality rate following rupture was 24%. The bleeding recurrence rate was 22% with related mortality of 52%. In multivariate analysis, a bilirubin level >17 micromol/L (HR 3.768; p = 0.006), bleeding recurrence (HR 5.400; p < 0.0001), and ICU admission after initial management (HR 8.199; p < 0.0001) were associated with in-hospital mortality. CONCLUSION: This European, multicenter, large-cohort study confirmed that the prognosis of ruptured HCC is poor with an overall mortality rate of 24%, despite important advances in endovascular techniques. Overall, the rate of bleeding recurrence was more than 20%, with a related high risk of mortality.

European experience of 573 liver resections for hepatocellular adenoma: a cross-sectional study by the AFC-HCA-2013 study group.

BACKGROUND: Hepatocellular adenoma (HCA) is a benign hepatic lesion that may be complicated by bleeding and malignant transformation. The aim of the present study is to report on large series of liver resections for HCA and assess the incidence of hemorrhage and malignant transformation. METHODS: A retrospective cross-sectional study, from 27 European high-volume HPB units. RESULTS: 573 patients were analyzed. The female: male gender ratio was 8:2, mean age: 37 ± 10 years. Of the 84 (14%) patients whose initial presentation was hemorrhagic shock (Hemorrhagic HCAs), hemostatic intervention was urgently required in 25 (30%) patients. No patients died after intervention. Tumor size was >5 cm in 74% in hemorrhagic HCAs and 64% in non-hemorrhagic HCAs (p < 0.001). In non-hemorrhagic HCAs (n = 489), 5% presented with malignant transformation. Male status and tumor size >10 cm were the two predictive factors. Liver resections included major hepatectomy in 25% and a laparoscopic approach in 37% of the patients. In non-hemorrhagic HCAs, there was no mortality and major complications occurred in 9% of patients. DISCUSSION: Liver resection for HCA is safe. Presentation with hemorrhage was associated with larger tumor size. In males with a HCA >10 cm, a HCC should be suspected. In such situation, a preoperative biopsy is preferable and an oncological liver resection should be considered.

Liver resection for hepatocellular carcinoma in patients with metabolic syndrome: A multicenter matched analysis with HCV-related HCC.

BACKGROUND & AIMS: The incidence of metabolic syndrome-related hepatocellular carcinoma (MS-HCC) is increasing worldwide. High resection risks are anticipated because of underlying steatohepatitis, but long-term results are unknown. To clarify the outcomes following liver resection in patients with MS-HCC and to compare the outcomes of MS-HCC to HCV-related HCC (HCV-HCC). METHODS: All the consecutive patients undergoing liver resection for HCC in six high-volume HPB units between 2000 and 2012 were retrospectively considered. The patients with MS-HCC were identified and matched one-to-one with HCV-HCC patients without metabolic syndrome. Matching was based on age, cirrhosis, Child-Pugh class, portal hypertension, HCC number and diameter and liver resection extension. RESULTS: Among 1563 patients undergoing liver resection for HCC in the study period, 96 (6.1%) had MS-HCC. They were matched with 96 HCV-HCC patients. All patients were Child-Pugh class A, 22.9% had cirrhosis. Forty-one patients per group (42.7%) required major hepatectomy. The MS-HCC group had a higher prevalence of steatohepatitis (25.0% vs. 9.4%, p=0.004). Operative mortality was 2.1% (1 MS-HCC, 3 HCV-HCC, p=0.621). Morbidity and liver failure rates were similar between the two groups. In the multivariate analysis, cirrhosis, major hepatectomy, and MELD >8, but not steatohepatitis, impacted severe morbidity and liver failure rates. The MS-HCC group had better 5-year overall survival (65.6% vs. 61.4%, p=0.031) and recurrence-free survival (37.0% vs. 27.5%, p=0.077). Independent negative prognostic factors were HCV-HCC, multiple HCC, microvascular invasion, and satellite nodules. CONCLUSIONS: Liver resection is safe for MS-HCC, as for HCV-HCC. Cirrhosis, but not steatohepatitis, affects short-term outcomes. MS-HCC is associated with excellent long-term outcomes, better than HCV-HCC.

Tumor location is a strong predictor of tumor progression and survival in T2 gallbladder cancer: an international multicenter study.

OBJECTIVE: To determine the prognostic impact of tumor location in gallbladder cancer. BACKGROUND: Depth of tumor is a strong predictor of survival after curative resection of gallbladder cancer. However, the gallbladder has a unique anatomical relationship with the liver, and the clinical significance of tumor location remains unclear. METHODS: For 437 patients with gallbladder cancer who underwent resection at 4 international institutions, clinicopathologic characteristics and their association with survival were analyzed. Tumor location was defined as "hepatic side" or "peritoneal side," and the prognostic significance of tumor location was evaluated. RESULTS: Among the 252 patients with T2 disease, patients with tumors on the hepatic side (T2h, n = 99) had higher rates of vascular invasion, neural invasion, and nodal metastasis than patients with tumors on the peritoneal side (T2p, n = 153) (51% vs 19%, 33% vs 8%, and 40% vs 17%, respectively; P < 0.01 for all). After a median follow-up of 58.9 months, 3-year and 5-year survival rates were 52.1% and 42.6%, respectively, for T2h tumors and 73.7% and 64.7%, respectively, for T2p tumors (P = 0.0006). No such differences were observed in T1 or T3 tumors. Multivariate analysis confirmed the independent association of hepatic-side location with survival in T2 tumors (hazard ratio, 2.7; 95% confidence interval, 1.7-4.2; P < 0.001). This subclassification of T2 tumors predicted recurrence in the liver (23% vs 3%; P = 0.003) and distant lymph nodes (16% vs 3%; P = 0.019) even after radical resection. CONCLUSIONS: After curative resection of T2 gallbladder cancer, tumor location predicts the pattern of recurrence and survival.

Lymph node metastases in patients undergoing surgery for a gallbladder cancer. Extension of the lymph node dissection and prognostic value of the lymph node ratio.

BACKGROUND: Lymph node (LN) status is one of the strongest prognostic factors after gallbladder cancer (GBC) resection. The adequate extension of LN dissection and the stratification of the prognosis in N+ patients have been debated. The present study aims to clarify these issues. METHODS: A total of 112 consecutive patients who underwent operations for GBC with LN dissection were analyzed. Twenty-five patients (22.3%) had D1 dissection (hepatic pedicle), and 87 (77.7%) had D2 dissection (hepatic pedicle, celiac and retro-pancreatic area). The LN ratio (LNR) was computed as follows: number of metastatic LNs/number of retrieved LNs. RESULTS: The median number of retrieved LNs was 7 (1-35). Fifty-nine patients (52.7%) had LN metastases (22 N2). D2 dissection allowed the retrieval of more LNs (8 vs. 3, p = 0.0007), with similar short-term outcomes. Common bile duct (CBD) resection (n = 41) did not increase the number of retrieved LNs. In five patients, D2 dissection identified skip LN metastases that otherwise would have been missed. LN metastases negatively impacted survival (5-years survival 57.2% if N0 vs. 12.4% if N+, p < 0.0001), but N1 and N2 patients had similar survival rates. The number of LN+ (1-3 vs. ≥4) did not impact prognosis. An LNR = 0.15 stratified the prognosis of N+ patients: 5-years survival 32.7% if LNR ≤ 0.15 vs. 10.3% if LNR > 0.15 (multivariate analysis p = 0.007). CONCLUSIONS: A D2 LN dissection is recommended in all patients, because it allows for better staging. CBD resection does not improve LN dissection. An LNR = 0.15, not the site of metastatic LNs, stratified the prognoses of N+ patients.

Nodular Regenerative Hyperplasia in Patients Undergoing Liver Resection for Colorectal Metastases After Chemotherapy: Risk Factors, Preoperative Assessment and Clinical Impact.

BACKGROUND: Nodular regenerative hyperplasia (NRH) is a severe form of chemotherapy-related liver injury (CALI) that may worsen the short-term outcome of liver resection (LR) for colorectal metastases (CRLM). The present study aimed to clarify the incidence, risk factors, preoperative assessment, and clinical impact of NRH. METHODS: Overall, 406 patients undergoing 478 LRs for CRLM after chemotherapy between 2000 and 2012 were studied. All resection specimens were reviewed. After Gomori staining, NRH was graded according to the Wanless score. RESULTS: NRH was diagnosed in 87 (18.2 %) patients, grades 2-3 in 14 (2.9 %) patients. At multivariate analysis, the prevalence of NRH was increased after oxaliplatin administration (21.4 vs. 8.4 %; p = 0.003), and reduced by the addition of bevacizumab (11.7 vs. 19.8 %; p = 0.020). Two parameters predicted the presence of NRH: the APRI score (AST to platelet ratio index: 25.5 % if >0.36 vs. 9.8 % if ≤0.36; p = 0.004), and the platelet count (63.6 % if <100 × 10(3)/mm(3) vs. 25.3 % if 100-200 × 10(3)/mm(3) vs. 11.9 % if >200 × 10(3)/mm(3); p = 0.032). Ninety-day mortality and liver failure rates were 0.6 and 3.6 %. NRH was an independent predictor of postoperative liver failure (9.2 % if present vs. 2.3 % if not present; p = 0.021). In patients with grades 2-3 NRH, the rate of liver failure was 14.3 %, 25.0 % after major hepatectomy. No other forms of CALI impacted short-term outcomes. CONCLUSIONS: NRH was the most relevant form of CALI, increasing the risk of postoperative liver failure. Oxaliplatin increased the incidence of NRH, while bevacizumab decreased it. The APRI score and platelet count were useful tools for predicting NRH.

Surgical management of advanced pancreatic neuroendocrine tumors: short-term and long-term results from an international multi-institutional study.

BACKGROUND: The role of extended resections in the management of advanced pancreatic neuroendocrine tumors (PNETs) is not well defined. METHODS: Between 1995 and 2012, 134 patients with PNET underwent isolated (isoPNET group: 91 patients) or extended pancreatic resection (synchronous liver metastases and/or adjacent organs) (advPNET group: 43 patients). RESULTS: The associated resections included 27 hepatectomies, 9 vascular resections, 12 colectomies, 10 gastrectomies, 4 nephrectomies, 4 adrenalectomies, and 3 duodenojejunal resections. R0 was achieved in 41 patients (95%) in the advPNET. The rates of T3-T4 (73 vs 16%; p < .0001) and N+ (35 vs 13%; p = .007) were higher in the advPNET group. Mortality (5 vs 2%) and major morbidity (21 vs 19%) rates were similar between the 2 groups. The 5-year overall survival (OS) of the series was 87% in the isoPNET group and 66% in the advPNET group (p = .006). Only patients with both locally advanced disease and liver metastases showed worse survival (p = .0003). The advPNET group developed recurrence earlier [disease-free survival (DFS) at 5 years: 26 vs 81%; p < .001]. In univariate analysis, negative prognostic factors of survival were: poor degree of differentiation (p < .001), liver metastasis (p = .011), NE carcinoma (p < .001), and resection of adjacent organs (p = .013). The multivariate analysis did not highlight any factor that influenced OS. In multivariate analysis independent DFS factors were a poor degree of differentiation (p = .03) and the European Neuroendocrine Tumor Society stage (p = .01). CONCLUSIONS: An aggressive surgical approach for locally advanced or metastatic tumors is safe and offers long-term survival.

Role of neoadjuvant chemotherapy in resectable synchronous colorectal liver metastasis; An international multi-center data analysis using LiverMetSurvey.

BACKGROUND AND OBJECTIVES: The use of neo-adjuvant chemotherapy in resectable synchronous liver metastasis is ill defined. The aim of this study was to evaluate neo-adjuvant chemotherapy on outcomes following liver resection for synchronous CLM. METHODS: An analysis of a multi-centric cohort from the LiverMetSurvey International Registry, who had undergone curative resections for synchronous CLM was undertaken. Patients who received neo-adjuvant chemotherapy prior to liver surgery (group NAS; n = 693) were compared with those treated by surgery alone (group SG; n = 608). Baseline clinicopathological variables were compared. Predictors of overall (OS) and disease free survival (DFS) were subsequently identified. RESULTS: Clinicopathological comparison of the groups revealed a greater proportion of solitary metastasis in the SG compared to the NAS group (58.8% versus 38.4%; P < 0.001) therefore a separate analysis of solitary versus multi-centric analysis was performed. N-stage (> N1), number of metastasis (> 3), serum CEA (> 5 ng/ml) and no adjuvant chemotherapy independently predicted poorer OS, while N-stage (> N1), serum CEA (> 5 ng/ml) and no adjuvant chemotherapy independently predicted poorer DFS. Neo-adjuvant chemotherapy did not independently affect outcome. CONCLUSION: We present an analysis of a large multi-center series of the role of neo-adjuvant chemotherapy in resectable CLM and demonstrate no survival advantage in this setting.

Ultrasound-guided laparoscopic liver resections.

BACKGROUND: Intraoperative liver ultrasound has an established role in liver surgery to complete staging and to guide resection. The same performances should be expected by laparoscopic ultrasound (LUS). METHODS: LUS is first performed to identify relationships between tumor and vasculo-biliary pedicles. The planes where the main vascular structures run are marked on the liver surface. Parenchymal transection is performed and each vessel recognized during LUS exploration is divided. RESULTS: From 01/2009 to 10/2013, in 61 out of 742 liver resections (8.2 %), a laparoscopic approach was attempted. The conversion rate was 9.8 % (six patients). No conversion was related to bleeding or intraoperative complications. The remnant 55 patients were affected by benign lesions in 11 cases and malignant tumors in 44. The resections included 3 left hepatectomies, 14 bisegmentectomies Sg2-3, 5 segmentectomies, and 38 wedge resections. Associated procedures were performed in eight patients (14.5 %), including four colorectal resections. Median duration of surgery was 150 min (60-345 min). Median operative blood loss was 100 mL (0-500 mL). Median size of resected tumor was 2.5 cm (0.9-8 cm). Median surgical margin in oncological resections was 7 mm (0-50 mm). Postoperative complications occurred in four patients (7.2 %), all grade 2 according to Dindo classification. No liver-related morbidity occurred. Median length of hospital stay was 5 days (3-9 days). CONCLUSIONS: Ultrasound-guided liver resections can be performed by laparoscopic approach with the same accuracy than open surgery.

Resection of liver metastases from colorectal mucinous adenocarcinoma: is this a different disease? Results of a case-control study.

OBJECTIVES: To compare outcomes following liver resection of colorectal metastases (CRLM) from mucinous adenocarcinoma (Muc-CRLM) versus nonmucinous adenocarcinoma (non-Muc-CRLM). BACKGROUND: Among colorectal adenocarcinomas, 10%-15% are mucinous and have worse prognoses than nonmucinous ones. Outcomes of liver resection for Muc-CRLM remain unknown. METHODS: Among 701 patients undergoing liver resection for CRLM between 1998 and 2012, 102 (14.6%) had Muc-CRLM. Each was matched with a non-Muc-CRLM patient, based on tumor N status, disease-free interval (DFI) between primary tumor and metastases, CRLM number and diameter, extrahepatic disease, and preoperative chemotherapy. RESULTS: Within the 2 groups, 69.6% of patients had N+ primary tumor, 72.5% had DFI of less than 12 months, 28.4% had 4 or more CRLM, and 22.5% had associated extrahepatic disease. 59.8% of patients received preoperative chemotherapy. Muc-CRLM patients had higher prevalences of right/transverse colon cancer (55.9% vs 29.4%; P<0.0001) and K-ras mutation (67 patients tested, 61.8% vs 36.4%; P=0.037), as well as lower response to preoperative chemotherapy (63.9% vs 85.2%; P=0.006). Multivariate analysis showed Muc-CRLM to have lower rates of 5-year overall (33.2% vs 55.2%; P=0.010) and disease-free survival (32.5% vs 49.3%; P=0.037). Muc-CRLM recurrence was more often peritoneal (20.3% vs 6.5%; P=0.024) and at multiple sites (47.5% vs 21.0%; P=0.002), and had lower rates of re-resection (16.9% vs 43.5%; P=0.002) and 3-year post-recurrence survival (11.7% vs 43.4%; P=0.0003). CONCLUSIONS: Muc-CRLM patients strongly differed from non-Muc-CRLM patients, showing a lower chemotherapy response and higher K-ras mutation prevalence. Muc-CRLM appears to be a separate disease, which is associated with worse survival and aggressive rarely re-resectable recurrences.

Early recurrence after liver resection for colorectal metastases: risk factors, prognosis, and treatment. A LiverMetSurvey-based study of 6,025 patients.

PURPOSE: The aims of this study were to assess the risk of early recurrence after liver resection for colorectal metastases (CRLM) and its prognostic value; identify early recurrence predictive factors; clarify the effect of perioperative chemotherapy on its occurrence; and elucidate the best early recurrence management. METHODS: Patients of the LiverMetSurvey registry who underwent complete liver resection (R0/R1) between 1998 and 2009 were reviewed. Early recurrence was defined as any recurrence that occurred within 6 months after resection. RESULTS: A total of 6,025 patients were included; 2,734 (45.4 %) had recurrence, including 639 (10.6 %) early recurrences. Early recurrence was mainly hepatic (59.5 vs. 54.4 % for late recurrences; p = 0.023). Independent risk factors of early recurrence were: T3-4 primary tumor (p = 0.0002); synchronous CRLM (p = 0.0001); >3 CRLM (p < 0.0001); 0-mm margin liver resection (p = 0.003); and associated intraoperative radiofrequency ablation (p = 0.0005). Response to preoperative chemotherapy (complete/partial) and administration of adjuvant chemotherapy reduced early recurrence risk (p = 0.003 and p < 0.0001, respectively). Intraoperative ultrasonography reduced hepatic early recurrence rate (p = 0.025). Early recurrence negatively affected prognosis: 5-year survival 26.9 versus 49.4 % for the late recurrence group (p < 0.0001, median follow-up 34.4 months). Overall, 234 (36.6 %) patients with early recurrence underwent re-resection. These patients had survival rates higher than non-re-resected patients (5-year survival 47.2 vs. 8.9 %; p < 0.0001) and similar to re-resected patients for late recurrence (48.7 %). Chemotherapy before early recurrence resection improved later survival (5-year survival 61.5 vs. 43.7 %; p = 0.028). CONCLUSIONS: Early recurrence risk is enhanced for extensive disease after poor preoperative disease control and inadequate surgical treatment, but is reduced after adjuvant chemotherapy. Although early recurrence negatively affects prognosis, re-resection may restore better survival. Chemotherapy before early recurrence resection is advocated.

Anti-cancer effect and gene modulation of ET-743 in human biliary tract carcinoma preclinical models.

BACKGROUND: Standard chemotherapy in unresectable biliary tract carcinoma (BTC) patients is based on gemcitabine combined with platinum derivatives. However, primary or acquired resistance is inevitable and no second-line chemotherapy is demonstrated to be effective. Thus, there is an urgent need to identify new alternative (chemo)therapy approaches. METHODS: We evaluated the mechanism of action of ET-743 in preclinical models of BTC. Six BTC cell lines (TFK-1, EGI-1, TGBC1, WITT, KMCH, HuH28), two primary cell cultures derived from BTC patients, the EGI-1 and a new established BTC patient-derived xenografts, were used as preclinical models to investigate the anti-tumor activity of ET-743 in vitro and in vivo. Gene expression profiling was also analyzed upon ET-743 treatment in in vivo models. RESULTS: We found that ET-743 inhibited cell growth of BTC cell lines and primary cultures (IC50 ranging from 0.37 to 3.08 nM) preferentially inducing apoptosis and activation of the complex DNA damage-repair proteins (p-ATM, p-p53 and p-Histone H2A.x) in vitro. In EGI-1 and patient-derived xenografts, ET-743 induced tumor growth delay and reduction of vasculogenesis. In vivo ET-743 induced a deregulation of genes involved in cell adhesion, stress-related response, and in pathways involved in cholangiocarcinogenesis, such as the IL-6, Sonic Hedgehog and Wnt signaling pathways. CONCLUSIONS: These results suggest that ET-743 could represent an alternative chemotherapy for BTC treatment and encourage the development of clinical trials in BTC patients resistant to standard chemotherapy.

Induction gemcitabine and oxaliplatin therapy followed by a twice-weekly infusion of gemcitabine and concurrent external-beam radiation for neoadjuvant treatment of locally advanced pancreatic cancer: a single institutional experience.

BACKGROUND: Chemoradiotherapy (CRT) may render curative resection feasible in patients with locally advanced pancreatic carcinoma (LAPC). The authors previously demonstrated the achievement of significant disease control and a median survival of 14 months by CRT in patients with LAPC. In this study, they evaluated the use of induction chemotherapy followed by a CRT neoadjuvant protocol. METHODS: Patients first received induction gemcitabine and oxaliplatin (GEMOX) (gemcitabine 1000 mg/m(2), oxaliplatin 100 mg/m(2)). Patients without disease progression then received gemcitabine twice weekly (50 mg/m(2) daily) concurrent with radiotherapy (50.4 grays) and were re-evaluated for resectability. RESULTS: Thirty-nine patients (15 with borderline resectable disease and 24 with unresectable disease) entered the study. The treatment was well tolerated. Disease control was obtained in 29 of 39 patients. Two patients progressed after GEMOX, and 7 progressed after CRT. After a median follow-up of 13 months, the median progression-free survival (PFS) was 10.2 months. The median PFS of patients with borderline resectable and unresectable disease was 16.6 and 9.1 months, respectively (P = .056). For the whole group, the median overall survival (OS) was 16.7 months (27.8 months for patients with borderline resectable disease, 13.3 for patients with unresectable disease; P = .045). Eleven patients (9 with borderline resectable disease and 2 with unresectable disease at diagnosis) underwent successful resection. Patients who underwent resection had a significantly longer median PFS compared with nonresected patients (19.7 months vs 7.6 months, respectively). The median OS among resected and nonresected patients was 31.5 months and 12.3 months, respectively (P < .001). CONCLUSIONS: The current results indicated that induction GEMOX followed by CRT is feasible in patients with LAPC. Both those with borderline resectable disease and those with unresectable disease received clinical benefit, a chance to obtain resectability, and improved survival. The authors concluded that this protocol warrants further evaluation.

Panitumumab in combination with infusional oxaliplatin and oral capecitabine for conversion therapy in patients with colon cancer and advanced liver metastases. The MetaPan study.

BACKGROUND: Preoperative chemotherapy improves the outcome in patients with colorectal cancer with liver metastases. In the current study, the authors evaluated the activity of a conversion treatment with the combination of capecitabine plus oxaliplatin (XELOX) used in association with panitumumab in patients with unresectable, liver-only, metastatic colon cancer. METHODS: Chemotherapy-naive patients with unresectable liver metastases from colon cancer with no other metastatic disease sites were enrolled. All patients received upfront therapy with XELOX plus panitumumab (P-XELOX) and were reevaluated for resectability every 4 cycles. The primary endpoint was the objective response rate (ORR). Secondary endpoints were overall survival (OS), progression-free survival, the percentage of patients whose disease became radically resectable, and the safety of the P-XELOX combination. RESULTS: A total of 49 patients were recruited, 35 of whom had wild-type KRAS (wtKRAS) and 14 of whom (who were enrolled before study amendment) had unknown (9 patients) or mutated (5 patients) KRAS mutational status. Forty-six patients were evaluable for response. After conversion P-XELOX therapy, the ORR in the general population was 54%, with 2 complete responses, 23 partial responses, and 14 cases of stable disease. In patients with wtKRAS, the ORR of the patients reached 65% (2 CRs and 19 PRs), which allowed 15 patients with initial unresectable liver metastasis to be reclassified as having resectable disease. Survival analysis demonstrated a median progression-free survival of 8.5 months and a median OS of 21.9 months. Patients who underwent surgery were found to have a significantly better OS when compared with those who did not undergo surgery (P < .001). Overall, toxicities were found to be predictable and manageable, with the most common being cutaneous, gastrointestinal, and neurologic toxicities. CONCLUSIONS: Conversion P-XELOX therapy yields high response and resectability rates for patients with metastatic colon cancer with extensive liver involvement.

Long-term effectiveness of resection and radiofrequency ablation for single hepatocellular carcinoma ≤3 cm. Results of a multicenter Italian survey.

BACKGROUND & AIMS: The aim of this study was to compare liver resection and radiofrequency ablation in patients with single hepatocellular carcinoma ≤3 cm and compensated cirrhosis. METHODS: The study involved 544 Child-Pugh A cirrhotic patients (246 in the resection group and 298 in the radiofrequency group) observed in 15 Italian centers. Overall survival and tumor recurrence rates were analyzed using the Kaplan Meier method before and after propensity score matching. Cox regression models were used to identify factors associated with overall survival and tumor recurrence. RESULTS: Two cases of perioperative mortality were observed in the resection group and the rate of major complications was 4.5% in the resection group and 2.0% in the radiofrequency group (p=0.101). Four-year overall survival rates were 74.4% in the resection group and 66.2% in the radiofrequency group (p=0.353). Four-year cumulative HCC recurrence rates were 56% in the resection group and 57.1% in the radiofrequency group (p=0.765). Local tumor progression was detected in 20.5% of ablated patients and in one resected patient (p<0.001). After propensity score matching, both survival and tumor recurrence were still not significantly different although a trend towards lower recurrence was observed in resected patients. Older age and higher alpha-fetoprotein levels were independent predictors of poor overall survival while older age and higher alanine-aminotransferase levels resulted to be independent factors associated with higher recurrence rate. CONCLUSIONS: In spite of a higher rate of local tumor progression, radiofrequency ablation can provide results comparable to liver resection in the treatment of single hepatocellular carcinoma ≤3 cm occurring in compensated cirrhosis.

Liver resection for colorectal metastases after chemotherapy: impact of chemotherapy-related liver injuries, pathological tumor response, and micrometastases on long-term survival.

OBJECTIVES: We analyzed the impact of chemotherapy-related liver injuries (CALI), pathological tumor regression grade (TRG), and micrometastases on long-term prognosis in patients undergoing liver resection for colorectal metastases after preoperative chemotherapy. BACKGROUND: CALI worsen the short-term outcomes of liver resection, but their impact on long-term prognosis is unknown. Recently, a prognostic role of TRG has been suggested. Micrometastases (microscopic vascular or biliary invasion) are reduced by preoperative chemotherapy, but their impact on survival is unclear. METHODS: Patients undergoing liver resection for colorectal metastases between 1998 and 2011 and treated with oxaliplatin and/or irinotecan-based preoperative chemotherapy were eligible for the study. Patients with operative mortality or incomplete resection (R2) were excluded. All specimens were reviewed to assess CALI, TRG, and micrometastases. RESULTS: A total of 323 patients were included. Grade 2-3 sinusoidal obstruction syndrome (SOS) was present in 124 patients (38.4%), grade 2-3 steatosis in 73 (22.6%), and steatohepatitis in 30 (9.3%). Among all patients, 22.9% had TRG 1-2 (major response), whereas 55.7% had TRG 4-5 (no response). Microvascular invasion was detected in 37.8% of patients and microscopic biliary infiltration in 5.6%.The higher the SOS grade the lower the pathological response: TRG 1-2 occurred in 16.9% of patients with grade 2-3 SOS versus 26.6% of patients with grade 0-1 SOS (P = 0.032).After a median follow-up of 36.9 months, 5-year survival was 38.6%. CALI did not negatively impact survival. Multivariate analysis showed that grade 2-3 steatosis was associated with better survival than grade 0-1 steatosis (5-year survival rate of 52.5% vs 35.2%, P = 0.002). TRG better than the percentage of viable cells stratified patient prognosis: 5-year survival rate of 60.4% in TRG 1-2, 40.2% in TRG 3, and 29.8% in TRG 4-5 (P = 0.0001). Microscopic vascular and biliary invasion negatively impacted outcome (5-year survival rate of 23.3% vs 45.7% if absent, P = 0.017; 0% vs 42.3%, P = 0.032, respectively). CONCLUSIONS: TRG was confirmed to be a crucial prognostic determinant. CALI do not negatively impact long-term prognosis, but the tumor response is reduced in patients with grade 2-3 SOS. Steatosis was found to have a protective effect on survival. Micrometastases significantly impacted prognosis assessment.

Measured versus estimated total liver volume to preoperatively assess the adequacy of the future liver remnant: which method should we use?

OBJECTIVES: To determine which method of liver volumetry is more accurate in predicting a safe resection. BACKGROUND: Before major or extended hepatectomy, assessment of the future liver remnant (FLR) is crucial to reduce the risk of postoperative hepatic insufficiency. The FLR volume is usually expressed as the ratio of FLR to nontumorous total liver volume (TLV), which can be measured directly by computed tomography (mTLV) or estimated (eTLV) on the basis of correlation existing with the body surface area. To date, these 2 methods have never been compared. METHODS: All consecutive, noncirrhotic patients who underwent resection of 3 or more liver segments between April 2000 and April 2012 and for whom (i) preoperative computed tomographic scans and (ii) body surface area were available entered the study. The mTLV (calculated as TLV - tumor volume) was compared with the eTLV (calculated as -794.41 + 1267.28 × body surface area) using volumetric data (cm) and clinical outcome measures (specifically, hepatic insufficiency and 90-day mortality). Definition of hepatic insufficiency was peak postoperative serum total bilirubin level of more than 7 mg/dL or, in jaundiced patients, an increasing bilirubin level on day 5 or thereafter. RESULTS: Two-hundred forty-three patients who had undergone major (n = 135) or extended (n = 108) hepatectomies met the inclusion criteria. Twenty-eight patients (11.5%) developed hepatic insufficiency, whereas 7 patients (2.9%) died postoperatively. Compared with the eTLV, the mTLV underestimated the liver volume in 60.1% of the patients (P < 0.01). Forty-seven and 73 patients had an inadequate FLR based on mTLV and eTLV, respectively. Portal vein occlusion (PVO) was used in 44 patients. In patients (n = 162) in whom both methods did not evidence the need for PVO, postoperative hepatic insufficiency and mortality were 4.9% and 0.6%, respectively. Conversely, in patients (n = 27) in whom the eTLV but not the mTLV evidenced the need for PVO, and thus PVO was not performed, hepatic insufficiency (22.2%; P = 0.001) and mortality (3.7%; P = ns) were higher. CONCLUSIONS: The use of eTLV identifies a subset of patients (∼11%) in whom liver volumetry with the mTLV underestimates the risk of hepatic insufficiency.

MACC1 mRNA levels predict cancer recurrence after resection of colorectal cancer liver metastases.

OBJECTIVE: Upon colon cancer metastasis resection in liver, disease outcome is heterogeneous, ranging from indolent to very aggressive, with early recurrence. The aim of this study is to investigate the capability of metastasis associated in colon cancer 1 (MACC1) levels measured in liver metastasis specimens to predict further recurrence of the disease. METHODS: Gene expression and gene dosage of MACC1, hepatocyte growth factor (HGF), and hepatocyte growth factor receptor (MET) were assessed using quantitative realtime polymerase chain reaction on a cohort of 64 liver metastasis samples from patients with complete follow-up of 36 months and detailed clinical annotation. The most relevant mutations associated to prognosis in colorectal cancer, KRAS, and PIK3CA were assessed on the same specimens with Sanger sequencing. RESULTS: Receiver operating characteristic (ROC) analysis revealed that MACC1 mRNA abundance is a good indicator of metastatic recurrence (AUC = 0.65, P < 0.05), whereas no such results were obtained with MET and HGF, nor with gene dosage. Generation of MACC1-based risk classes was capable of successfully separating patients into poor and good prognosis subgroups [hazard ratio (HR) = 5.236, 95% confidence interval (CI) = 1.2068-22.715, P < 0.05]. Also KRAS mutation was significantly associated with higher risk of recurrence (HR = 2.07, 95% CI = 1.048-4.09, P < 0.05). Cox regression multivariate analysis supported the independence of MACC1, but not KRAS, from known prognostic clinical information (Node Size HR = 3.155, 95% CI = 1.4418-6.905, P < 0.001, Preoperative carcinoembryonic antigen HR = 2.359, 95% CI = 1.0203-5.452, P < 0.05, MACC1 HR = 7.2739, 95% CI = 1.6584-31.905, P < 0.01). CONCLUSIONS: MACC1, a new easily detectable biomarker in cancer, is an independent prognostic factor of recurrence after liver resection of colorectal cancer metastasis.

A snapshot of the effective indications and results of surgery for hepatocellular carcinoma in tertiary referral centers: is it adherent to the EASL/AASLD recommendations?: an observational study of the HCC East-West study group.

OBJECTIVE: The aim of this study was to investigate in a retrospective setting the patients' profile and results of those undergoing surgery for hepatocellular carcinoma (HCC) in high-volume surgical centers throughout the world. BACKGROUND: Whether surgery for HCC is a suitable approach and for which subset of patients is still controversial. The EASL/AASLD (European Association for the Study of Liver Disease/American Association for the Study of Liver Disease) guidelines, based on the Barcelona Clinic Liver Cancer (BCLC) classification, leave little room for hepatic resection; inversely, other reports promote its wider application. METHODS: On the basis of the network "Hepatocellular Carcinoma: Eastern & Western Experiences," data for 2046 consecutive patients resected for HCC in 10 centers were collected. According to the BCLC classification, 1012 (50%) were BCLC 0-A, 737 (36%) BCLC B, and 297 (14%) BCLC C. Analysis of overall survival and disease-free survival and multivariate analysis of prognostic factors were performed. FINDINGS: The 90-day mortality rate was 2.7%. Overall morbidity was 42%. After a median follow-up of 25 months (range, 1-209 months), the 1-, 3-, and 5-year overall survival rates were 95%, 80%, and 61% for BCLC 0-A; 88%, 71%, and 57% for BCLC B; and 76%, 49%, and 38% for BCLC C (P = 0.000). The 1-, 3-, and 5-year disease-free survival rates were as follows: 77%, 41%, and 21% for BCLC 0-A; 63%, 38%, and 27% for BCLC B; and 46%, 28%, and 18% for BCLC C (P = 0.000). The multivariate analysis identified bilirubin, cirrhosis, esophageal varices, tumor size, and macrovascular invasion to be statistical and independent prognostic factors for overall survival. CONCLUSIONS: This large multicentric survey shows that surgery is in current practice widely applied among patients with multinodular, large, and macrovascular invasive HCC, providing acceptable short- and long-term results and justifying an update of the EASL/AASLD therapeutic guidelines in this sense.

Surgical management of congenital intrahepatic bile duct dilatation, Caroli's disease and syndrome: long-term results of the French Association of Surgery Multicenter Study.

OBJECTIVE: To assess clinical presentation and long-term results of surgical management of congenital intrahepatic bile duct dilatation (IHBDD) (Caroli disease and syndrome) in a multicenter setting. BACKGROUND: Congenital IHBDD predisposes to biliary stasis, resulting in intrahepatic lithiasis, septic complications, and cholangiocarcinoma. Although liver resection (LR) is considered to be the treatment of choice for unilobar disease extent into the liver, the management of bilobar disease and/or associated congenital hepatic fibrosis remains challenging. METHODS: From 1978 to 2011, a total of 155 patients (median age: 55.7 years) were enrolled from 26 centers. Bilobar disease, Caroli syndrome, liver atrophy, and intrahepatic stones were encountered in 31.0%, 19.4%, 27.7%, and 48.4% of patients, respectively. A complete resection of congenital intrahepatic bile ducts was achieved in 90.5% of the 148 patients who underwent surgery. RESULTS: Postoperative mortality was nil after anatomical LR (n = 111) and 10.7% after liver transplantation (LT) (n = 28). Grade 3 or higher postoperative morbidity occurred in 15.3% of patients after LR and 39.3% after LT. After a median follow-up of 35 months, the 5-year overall survival rate was 88.5% (88.7% after LT), and the Mayo Clinic score was considered as excellent or good in 86.0% of patients. The 1-year survival rate was 33.3% for the 8 patients (5.2%) who presented with coexistent cholangiocarcinoma. CONCLUSIONS: LR for unilobar and LT for diffuse bilobar congenital IHBDD complicated with cholangitis and/or portal hypertension achieved excellent long-term patient outcomes and survival. Because of the bad prognosis of cholangiocarcinoma and the sizeable morbidity-mortality after LT, timely indication for surgical treatment is of major importance.