Proposal of an integrated staging system using albumin-bilirubin grade and serum alpha-fetoprotein values for predicting postoperative prognosis of recurrent hepatocellular carcinoma.

BACKGROUND: Because repeat hepatectomy for recurrent hepatocellular carcinoma is a potentially invasive procedure, it is necessary to identify patients who truly benefit from repeat hepatectomy. Albumin-bilirubin grading has been reported to predict survival in patients with hepatocellular carcinoma. However, as prognosis also depends on tumor factors, a staging system that adds tumor factors to albumin-bilirubin grading may lead to a more accurate prognostication in patients with recurrent hepatocellular carcinoma. METHODS: Albumin-bilirubin grading and serum alpha-fetoprotein levels were combined and the albumin-bilirubin-alpha-fetoprotein score was created ([albumin-bilirubin grading = 1; 1 point, 2 or 3; 2 points] + [alpha-fetoprotein<75 ng/mL, 0 points; ≥5, 1 point]). Patients were classified into three groups, and their characteristics and survival were evaluated. The predictive ability of the albumin-bilirubin-alpha-fetoprotein score was compared with that of the Cancer of the Liver Italian Program and the Japan Integrated Stage scores. RESULTS: Albumin-bilirubin-alpha-fetoprotein score significantly stratified postoperative survival (albumin-bilirubin-alpha-fetoprotein score = 1/2/3: 5-year recurrence-free survival [%]: 22.4/20.7/0.0, p < 0.001) and showed the highest predictive value for survival among the integrated systems (albumin-bilirubin-alpha-fetoprotein score/Japan Integrated Stage/Cancer of the Liver Italian Program: 0.785/0.708/0.750). CONCLUSIONS: Albumin-bilirubin-alpha-fetoprotein score is useful for predicting the survival of patients with recurrent hepatocellular carcinoma undergoing repeat hepatectomy.

Neoadjuvant and Adjuvant Chemotherapy for Pancreatic Adenocarcinoma: Literature Review and Our Experience of NAC-GS.

In addition to established evidence of the efficacy of adjuvant chemotherapy (AC) for pancreatic ductal adenocarcinoma (PDAC), evidence of the effects of neoadjuvant treatments (NATs), including chemotherapy and chemoradiotherapy, has also been accumulating. Recent results from prospective studies and meta-analyses suggest that NATs may be beneficial not only for borderline resectable PDAC, but also for resectable PDAC, by increasing the likelihood of successful R0 resection, decreasing the likelihood of the development of lymph node metastasis, and improving recurrence-free and overall survival. In addition, response to NAT may be informative for predicting the clinical course after preoperative NAT followed by surgery; in this way, the postoperative treatment strategy can be revised based on the effect of NAT and the post-neoadjuvant therapy/surgery histopathological findings. On the other hand, the response to NAT and AC is also influenced by the tumor biology and the patient's immune/nutritional status; therefore, planning of the treatment strategy and meticulous management of NAT, surgery, and AC is required on a patient-by-patient basis. Our experience of using gemcitabine plus S-1 showed that this NAT regimen achieved tumor shrinkage and decreased the levels of tumor markers but failed to provide a survival benefit. Our results also suggested that response/adverse events to NAT may be predictive of the efficacy of AC, as well as survival outcomes.

Comparative analysis of perioperative and long-term outcomes of patients with hepatocellular carcinoma: Nonalcoholic fatty liver disease versus viral hepatitis.

BACKGROUND: Despite the accumulating evidence regarding the oncological differences between nonalcoholic fatty liver disease (NAFLD)-related hepatocellular carcinoma (HCC) and viral infection-related HCC, the short- and long-term outcomes of surgical resection of NAFLD-related HCC remain unclear. While some reports indicate improved postoperative survival in NAFLD-related HCC, other studies suggest higher postoperative complications in these patients. METHODS: Patients with NAFLD and those with hepatitis viral infection who underwent hepatectomy for HCC at our department were retrospectively analyzed. The clinical, surgical, pathological, and survival outcomes were compared between the two groups. RESULTS: Among the 1047 consecutive patients who underwent hepatectomy for HCC, 57 had NAFLD-related HCC (NAFLD group), and 727 had virus-related HCC (VH group). The body mass index and serum glycated hemoglobin levels were significantly higher in the NAFLD group than in the VH group. There were no significant differences in operative time and bleeding amount. Moreover, the morbidity and the length of postoperative hospital stays were similar across both groups. The pathological results showed that the tumor size was significantly larger in the NAFLD group than in the VH group. No significant differences between the groups in overall or recurrence-free survival were found. In a subgroup analysis with matched tumor diameters, patients in the NAFLD group had a better prognosis after hepatectomy than those in the VH group. CONCLUSION: Surgical outcomes after hepatectomy were comparable between the groups. Subgroup analysis reveals early detection and surgical intervention in NAFLD-HCC may improve prognosis.

Micro-hepatocellular carcinoma with bile duct tumor thrombus mimicking intrahepatic intraductal papillary neoplasm of the bile duct: a case report.

BACKGROUND: Microhepatocellular carcinoma with a gross bile duct tumor thrombus is extremely rare, making the correct preoperative diagnosis difficult. CASE PRESENTATION: A 78-year-old man was referred to our department for close examination of a liver tumor that was incidentally detected using ultrasonography. Blood tests revealed normal levels of tumor markers. Abdominal ultrasonography showed a 2-cm-sized hyperechoic mass with indistinct borders and hypoechoic margins at the origin of the right hepatic duct. Dynamic computed tomography showed a tumor with arterial phase predominance, a heterogeneous contrast effect, and prolonged enhancement. Cystic structures were observed in the tumors. In addition, localized dilatation of the caudate lobe bile duct was observed near the tumor. Cholangiography showed that the common bile duct, right and left hepatic ducts, and secondary branches did not have dilatation or stenosis. Biopsies of the bile duct revealed no malignancy. Under suspicion of intrahepatic intraductal papillary neoplasm of the bile duct, right hemi-hepatectomy was performed. The extrahepatic bile duct was preserved, because no tumor was found at the margin of the right hepatic duct during intraoperative frozen diagnosis. Macroscopically, the lesion was an 18 × 15 mm tumor occupying a dilated intrahepatic bile duct near the right hepatic duct, with a soft, fine papillary tumor. Based on morphology and immunostaining, tumor matched with moderately differentiated hepatocellular carcinoma. In addition, a 2 mm-sized hepatocellular carcinoma was observed in the liver parenchyma near the bile duct, where the tumor was located. CONCLUSIONS: Based on these findings, the patient was diagnosed with small hepatocellular carcinoma with a gross bile duct tumor thrombus. The cystic part seen on the preoperative images was considered as a gap between the bile duct and the tumor thrombus. The patient recovered well with no signs of recurrence 20 months after surgery.

Extensive extracranial growth of spheno-orbital meningioma: illustrative case.

BACKGROUND: Spheno-orbital meningioma (SOM) typically presents with a classic triad of symptoms (i.e., proptosis, visual impairment, and ocular paresis), resulting from intraorbital tumor invasion. The authors present a very rare case of SOM in which the chief complaint was swelling of the left temporal region, which, to the best of their knowledge, has not been reported previously. OBSERVATIONS: The patient presented with marked extracranial extension to the left temporal region but unremarkable intraorbital extension, even on radiological examination. Physical examination of the patient showed almost no exophthalmos or restriction of left eye movement, consistent with the radiological findings. Four separate meningioma specimens were removed by extraction (i.e., one each from the intracranial, extracranial, and intraorbital segments of the tumor and one from the skull). The World Health Organization grade was 1 and the MIB-1 index was less than 1%, indicating a diagnosis of a benign tumor. LESSONS: SOM may be present even in patients with only temporal swelling and few ocular-related symptoms, and detailed imaging evaluations may be required to identify the tumor.

Validation of quantitative prognostic prediction using ADV score for resection of hepatocellular carcinoma: A Korea-Japan collaborative study with 9200 patients.

BACKGROUND: A score derived from the concentrations of α-fetoprotein (AFP) and des-γ-carboxy prothrombin (DCP) and tumor volume (TV), called ADV score, has been shown to be prognostic of hepatocellular carcinoma (HCC) recurrence following hepatic resection (HR) or liver transplantation. METHODS: This multicenter, multinational validation study included 9200 patients who underwent HR from 2010 to 2017 at 10 Korean and 73 Japanese centers, and were followed up until 2020. RESULTS: AFP, DCP, and TV showed weak correlations (ρ ≤ .463, r ≤ .189, p < .001). Disease-free survival (DFS), overall survival (OS), and post-recurrence survival rates were dependent on 1.0 log and 2.0 log intervals of ADV scores (p < .001). Receiver operating characteristic (ROC) curve analysis showed that ADV score cutoffs of 5.0 log for DFS and OS yielded the areas under the curve ≥ .577, with both being significantly prognostic of tumor recurrence and patient mortality at 3 years. ADV score cutoffs of ADV 4.0 log and 8.0 log, derived through K-adaptive partitioning method, showed higher prognostic contrasts in DFS and OS. ROC curve analysis showed that an ADV score cutoff of 4.2 log was suggestive of microvascular invasion, with both microvascular invasion and an ADV score cutoff of 4.2 log showing similar DFS rates. CONCLUSIONS: This international validation study demonstrated that ADV score is an integrated surrogate biomarker for post-resection prognosis of HCC. Prognostic prediction using ADV score can provide reliable information that can assist in planning treatment of patients with different stages of HCC and guide individualized post-resection follow-up based on the relative risk of HCC recurrence.

Total Steroid Intake is Associated With Hospital Mortality in Patients With Pan-Peritonitis due to Colorectal Perforation.

BACKGROUND: Patients with pan-peritonitis (PP) due to colorectal perforation have high mortality rate because colorectal perforation causes septic shock. The association between total steroid intake (TSI) and hospital mortality of such patients is not clear. METHODS: One hundred forty-two patients who underwent surgery for PP due to colorectal perforation were reviewed. Patients were divided into two groups by 8000 mg of TSI. The cut-off value of TSI was determined using a receiver operating characteristic curve for hospital mortality. RESULTS: The cut-off value of TSI for hospital mortality was 8000 mg. Patients with TSI>8000 mg had high rate of hemodialysis, hospital mortality, and elevated neutrophil ratio (>95%) compared with those with TSI≤8000 mg. Multivariate analyses revealed that TSI (>8000/≤8000, mg) (OR, 9.669; 95% CI, 1.011-92.49; P = .049) was significantly associated with hospital mortality as well as bleeding volume (>1000/≤1000, mL) (OR, 26.08; 95% CI, 3.566-190.4; P = .001), lymphocyte ratio (≤4/>4, %) (OR, 7.988; 95% CI, 1.498-42.58; P = .015) and C-reactive protein (≤7.5/>7.5, mg/dL) (OR, 41.66; 95% CI, 4.784-33.33; P = .001). DISCUSSION: There was a significant association between TSI and hospital mortality in patients with PP due to colorectal perforation as well as intraoperative bleeding and systemic inflammatory markers.

Local transplantation of syngeneic adipose stromal vascular fraction ameliorates damaged anal sphincter function in a rat model of vaginal distension.

BACKGROUND: The adipose stromal vascular fraction contains abundant mesenchymal stem cells and is utilized for cell therapy of male stress urinary incontinence. The purpose of this paper was to explore the effect of local transplantation of the stromal vascular fraction on improvement of damaged anal sphincter function. METHODS: A rat model of vaginal distension was used as a model of damaged anal sphincter function. The adipose stromal vascular fraction was separated from the inguinal fat of syngeneic green fluorescent protein transgenic rats and delivered into the internal anal sphincter of vaginal distension rats. The maximum resting pressure was evaluated during insertion and withdrawal of the catheter at 4 or 10 days after vaginal distension treatment to estimate anal sphincter function. Green fluorescent protein-transfected human-adipose-derived mesenchymal stem cells were transplanted into the internal anal sphincter of nude rats. Hematoxylin-eosin and Masson trichrome staining were performed to evaluate tissue damage and collagen synthesis. Transplanted cells were identified using a green fluorescent protein antibody and a human-specific antibody. Activation of the transplanted human-ADSC was evaluated by quantitative RT-PCR RESULTS: The mean maximum resting pressure (during catheter withdrawal) of vaginal distension rats was significantly lower than that of control rats, and stromal vascular fraction injection normalized it 4 days after treatment (control: 5.66 ± 0.98, vaginal distension: 4.04 ± 1.28, vaginal distension + stromal vascular fraction: 5.92 ± 1.28 [mmHg, control versus vaginal distension: P = .039; vaginal distension versus vaginal distension + stromal vascular fraction: P = .007]). Histological examination showed that vaginal distension disrupted the internal anal sphincter, and the transplanted syngeneic stromal vascular fraction survived for 10 days. Transplanted xenogeneic human-adipose-derived mesenchymal stem cells survived in the internal anal sphincter of nude rats for 4 and 10 days. Genes related to extracellular remodeling were up-regulated in the transplanted human-adipose-derived mesenchymal stem cells CONCLUSION: Syngeneic and heterotopic transplanted adipose-derived mesenchymal stem cells engrafted in the internal anal sphincter and ameliorated damaged anal sphincter function in a rat model of vaginal distension.

Laparoscopic surgery reduced frequency of postoperative small bowel obstruction, and hospital stay compared with open surgery in a cohort of patients with colorectal cancer: a propensity score matching analysis.

BACKGROUND: Laparoscopic surgery (LS) is reported to reduce postoperative complications and hospital stay compared with open surgery (OP). Because patient selection may have been biased in previous studies, propensity score matching (PSM) analysis was used in this study to test the benefits of LS compared with OP. METHODS: A total of 759 patients with stage I-III colorectal cancer undergoing curative surgery were retrospectively reviewed. To minimize confounding bias between LS and OP groups, a 1:1 PSM analysis was performed based on adjuvant chemotherapy, age, albumin, body mass index, American Society of Anesthesiologists physical status depth of tumor, gender, lymph node dissection, maximum tumor size, obstructive tumor, previous abdominal surgery, pathological stage, tumor differentiation, and tumor location. Statistical analyses including chi-square test, Mann-Whitney U test, univariate analyses and Kaplan-Meier method and log-rank test were performed using the data after PSM to investigate the benefits of LS compared with OP. RESULTS: After PSM analysis, 460 patients remained in the study. The LS group had lower intraoperative blood loss (34 ± 70 vs 237 ± 391, mL; P < 0.001), lower frequency of postoperative small bowel obstruction (SBO) (17/213 vs 30/230; P = 0.045), lower rate of nasogastric tube insertion (7/223 vs 17/213; P = 0.036), and shorter postoperative hospital stay (13 ± 10 vs 25 ± 47, day; P < 0.001) than the OP group. Univariate analyses showed that LS significantly reduced the risk of postoperative SBO (odds ratio [OR] 0.532; 95% confidence interval [CI] 0.285-0.995; P = 0.048) and nasogastric tube insertion (OR 0.393; 95% CI 0.160-0.967; P = 0.042) compared with OP. There were no significant differences in OS and RFS between the groups. CONCLUSIONS: LS reduced intraoperative blood loss, frequency of postoperative SBO, rate of nasogastric tube insertion, and postoperative hospital stay compared with OP.

Mixed adenoneuroendocrine carcinoma of the non-ampullary duodenum with mismatch repair deficiency: a rare case report.

A non-ampullary duodenal mixed adenoneuroendocrine carcinoma (MANEC), consisting of a conventional adenocarcinoma and a neuroendocrine carcinoma (NEC), is exceedingly rare. Moreover, mismatch repair (MMR) deficient tumors have recently attracted attention. The patient, a 75-year-old woman with epigastric pain and nausea, was found to have a type 2 tumor of the duodenum, which was diagnosed on biopsy as a poorly differentiated carcinoma. A pancreaticoduodenectomy specimen showed a well-defined 50 × 48 mm tumor in the duodenal bulb, which was morphologically composed of glandular, sheet-like, and pleomorphic components. The glandular component was a tubular adenocarcinoma, showing a MUC5AC-positive gastric type. The sheet-like component consisted of homogenous tumor cells, with chromogranin A and synaptophysin diffusely positive, and a Ki-67 index of 72.8%. The pleomorphic component was diverse and prominent atypical tumor cells proliferated, focally positive for chromogranin A, diffusely positive for synaptophysin, and the Ki-67 index was 67.1%. The sheet-like and pleomorphic components were considered NEC, showing aberrant expression of p53, retinoblastoma, and p16. Notably, all three components were deficient in MLH1 and PMS2. We diagnosed a non-ampullary duodenal MANEC with MMR deficiency. This tumor has a unique morphology and immunohistochemical profile, and is valuable for clarifying the tumorigenesis mechanism of a non-ampullary duodenal MANEC.

The preoperative pan-immune-inflammation value is a novel prognostic predictor for with stage I-III colorectal cancer patients undergoing surgery.

PURPOSE: The pan-immune-inflammation value (PIV) is useful for stratifying outcomes in patients with metastatic colorectal cancer. However, it is unclear whether preoperative PIV can predict the surgical outcomes of patients with stage I-III colorectal cancer who receive surgery. METHODS: The records of 758 patients with stage I-III colorectal cancer who received surgical treatment were retrospectively reviewed. The preoperative PIV was calculated as follows: (neutrophil count × platelet count × monocyte count)/lymphocyte count. The cut-off value was determined using a receiver operating characteristic curve for overall survival. RESULTS: The cut-off value of the preoperative PIV was 376. Five hundred sixty-eight patients (74.9%) had low values (≤ 376), and 190 (25.1%) had high values (> 376). Univariate and multivariate analyses revealed that the PIV (> 376/ ≤ 376) (HR 2.485; 95% CI 1.552-3.981, P < 0.001) was significantly associated with overall survival, as well as age (> 60/ ≤ 60, years) (HR 1.988; 95% CI 1.038-3.807, P = 0.038), globulin-to-albumin ratio (> 0.83/ ≤ 0.83) (HR 2.013; 95% CI 1.231-3.290, P = 0.005) and postoperative complication (C-D grade III-V/0-II) (HR 1.991; 95% CI 1.154-3.438, P = 0.013). The Kaplan-Meier method and log-rank test showed significant differences in overall survival between patients with stage I-III disease with high (> 376) and low (≤ 376) PIVs. CONCLUSION: The preoperative PIV is useful for predicting surgical outcomes in patients with stage I-III colorectal cancer.

Prognostic significance of preoperative hyaluronic acid level in patients with hepatocellular carcinoma.

BACKGROUND: Serum hyaluronic acid (HA) levels are increased in patients with solid tumors, and may predict outcomes. However, as HA levels also correlate with the degree of liver fibrosis, the prognostic significance of serum HA levels in patients with hepatocellular carcinoma (HCC) is unclear. METHODS: A total of 656 consecutive patients who underwent hepatic resection for HCC were divided into two groups by serum HA level (high HA [≥200 ng/mL], n = 248; low HA [<200 ng/mL], n = 408). Clinicopathological characteristics and postoperative survival were compared between groups. Moreover, 1:1 propensity score matching analysis was applied to adjust characteristics between groups. RESULTS: Both the 5-year overall and relapse-free survival rates (OSR and RFSR) in the low HA group were significantly better than those in the high HA group (59.8% vs. 38.6%, respectively, p < 0.001 and 24.5% vs. 13.1%, respectively, p < 0.001). After propensity score matching, two comparable groups of 124 patients each were obtained. However, both the 5-year OSR and RFSR in the low HA group remained significantly better than those in the high HA group (57.4% vs. 38.3%, respectively, p = 0.006 and 22.5% vs. 14.7%, respectively, p = 0.003). CONCLUSION: High preoperative HA level predicts poor postoperative survival of patients with HCC. undergoing hepatic resection.

Postoperative Complications Associated With Intra- Versus Extracorporeal Anastomosis for Laparoscopic Right Colectomy.

OBJECTIVE: To compare the postoperative complications of intracorporeal anastomosis (ICA) and extracorporeal anastomosis (ECA) in patients undergoing laparoscopic right colectomy (LRC). BACKGROUND: Although several studies have compared postoperative complications of ICA and ECA after LRC, most were retrospective studies. METHODS: We performed a comprehensive electronic search of the literature to identify studies that compared postoperative complications between ICA and ECA in patients who underwent LRC. We performed meta-analysis using random-effects models to calculate the risk ratio (RR) and 95% confidence interval (CI) of experiencing complications, and we analyzed heterogeneity using I2 statistics. RESULTS: Fifteen studies consist of randomized controlled trials, case-control studies, and propensity score matching studies involving a total of 3219 patients who underwent LRC were included. Among 1377 patients who received ICA, 255 (18.5%) had postoperative complications, whereas among 1652 patients who received ECA, 373 (22.6%) had such complications. The results of the meta-analysis revealed that ICA was associated with a significantly reduced risk of postoperative complications (RR, .73; 95% CI: .57-.95; P = .02; I2 = 57%) compared with ECA. Although there was no significant difference between the 2 groups in risk of anastomotic leakage (RR, .67; 95% CI: .39-1.17; P = .16; I2 = 8%), there was a significant difference between them in risk of surgical site infection (RR, .50; 95% CI: .34-.71; P = .0002; I2 = 0%). CONCLUSIONS: Intracorporeal anastomosis is associated with a reduced risk of postoperative complications compared with ECA in patients undergoing LRC.

Significance of cytoplasmic expression of telomerase reverse transcriptase in patients with hepatocellular carcinoma undergoing liver resection.

Telomerase reverse transcriptase (TERT) is reportedly expressed in various types of cancer. However, to the best of our knowledge, the significance of subcellular expression of TERT in hepatocellular carcinoma (HCC) has not been evaluated in detail. The present study evaluated TERT expression in resected HCC tumor tissues using immunohistochemistry. TERT expression was assessed in both the cytoplasm and the nucleus of HCC cells. The associations between TERT expression and clinical characteristics, including expression levels of DNA-dependent protein kinase catalytic unit (DNA-PKcs) and 8-hydroxyganosine (8-OHdG), were investigated. Among the 135 HCCs, TERT expression was positive only in the cytoplasm in 86 tumors (63.7%), was positive only in the nucleus in 3 tumors (2.2%), was positive in both the cytoplasm and the nucleus in 5 tumors (3.7%) and was negative in 41 tumors (30.4%). Similar results were confirmed using another antibody for TERT. Cytoplasmic TERT expression was markedly associated with hepatitis B surface antigen, poor tumor differentiation, and expression levels of DNA-PKcs and 8-OHdG. However, TERT expression in the cytoplasm or in the nucleus was not significantly associated with the overall or recurrence-free survival periods. In conclusion, TERT was mainly expressed in the cytoplasm of HCC tissues. Cytoplasmic TERT expression was closely associated with hepatitis B virus-related HCC and DNA-PKcs expression, as well as oxidative stress.

Clinical Predictors of Unresectable Disease at Laparotomy in Patients With Pancreatic Ductal Adenocarcinoma Planning to Undergo Surgical Resection.

BACKGROUND/AIM: Computed tomography and positron emission tomography cannot detect all minute distant metastases and fully evaluate extensive vascular invasion in patients with pancreatic ductal adenocarcinoma (PDAC). The aim of this study was to investigate predictors of laparotomy only and palliative surgery in PDAC patients planning surgical resection. PATIENTS AND METHODS: We reviewed 239 PDAC patients planning surgical resection. Patients were divided into two groups based on resection status. Multivariate analyses were performed to identify predictors of unresectable disease at laparotomy. RESULTS: Twenty-five patients had unresectable disease at laparotomy. Multivariate analysis revealed that anatomical borderline resectable status (yes/no) (HR=5.458, p=0.012), pretreatment CA19-9 (>260/≤260 ng/ml) (HR=4.907, p=0.041), and tumor size (>25/≤25 mm) (HR=21.42, p=0.004) were associated with unresectable disease at laparotomy. CONCLUSION: Borderline resectable status, pretreatment CA19-9, and tumor size were closely associated with unresectable disease at laparotomy in PDAC patients planning surgical resection.

Efficacy and Feasibility of Adjuvant Gemcitabine Plus Cisplatin Chemotherapy After Major Hepatectomy for Biliary Tract Cancer.

BACKGROUND/AIM: The efficacy and feasibility of gemcitabine plus cisplatin (GC) chemotherapy in an adjuvant setting is unclear in patients with biliary tract cancer (BTC) undergoing major hepatectomy. PATIENTS AND METHODS: Patients with BTC who underwent major hepatectomy between 2008 and 2018 were included. Patients who received adjuvant chemotherapy (AC) were then divided into two groups: a GC group and a gemcitabine (GEM) alone group. AC-related factors and patient outcomes were investigated. RESULTS: Fifty (GC: 28, GEM: 22) patients received AC, and 33 patients did not. No difference in completion rate, relative dose intensity, or adverse events was seen between the two AC groups. Multivariate analysis revealed that AC with GC was an independent predictor of improved survival and reduction of early recurrence. CONCLUSION: AC with GC is tolerable and associated with better outcomes in patients with BTC who have undergone major hepatectomy.

Arterial chemoembolisation with cisplatin versus epirubicin for hepatocellular carcinoma (ACE 500 study): A multicentre, randomised controlled phase 2/3 trial.

BACKGROUND: Transarterial chemoembolisation (TACE) is a treatment option for hepatocellular carcinoma (HCC), but the optimum agent for TACE remains unclear. We compared the efficacy of TACE with cisplatin versus with epirubicin in patients with unresectable HCC. METHODS: This multicentre, randomised, phase 2/3 trial was performed at 21 hospitals in Japan. Patients with liver-confined HCC, performance status 0-2, and Child-Pugh class A/B were randomised to receive TACE with cisplatin or epirubicin. Patients were stratified in accordance with the institution, Child-Pugh class, tumour size, tumour thrombosis, α-fetoprotein and prior treatment. The primary end-point was overall survival in the intention-to-treat population. Tumour response was evaluated in accordance with the Response evaluation criteria in solid tumours criteria. FINDINGS: Between 2008 and 2012, 455 patients were randomly assigned to undergo TACE with cisplatin (n = 228) or epirubicin (n = 227). Eleven patients were ineligible, and 444 patients were included in the full analysis. Twelve patients not receiving TACE were excluded, and 432 patients were included in the safety analysis set. In phase 2, disease control rates in cisplatin (91·7%) and epirubicin (91·8%) groups exceeded the predefined threshold of 70%, and the study proceeded to phase 3. After a median follow-up of 32·7 months (IQR = 15·3-49·3), median overall survival periods were 2·93 years (95% CI 2·60-3·79) and 2·74 years (95%CI 2·26-3·21), respectively (hazard ratio 0·90 [95% CI 0·71-1·15], p = 0·22). Median times to treatment failure were 1·38 and 1·46 years (hazard ratio 1·09 [95% CI 0·88-1·35], p = 0·88), response rates were 65·3% and 60·6% (p = 0·31), and serious adverse event rates were 49·8% and 48·3% (p = 0·56), respectively. No treatment-related deaths occurred in either group. INTERPRETATION: In our phase 2/3 randomised trial, cisplatin is not significantly superior to epirubicin in TACE for patients with HCC.