Tadatoshi Takayama

Risk factors contributing to early and late phase intrahepatic recurrence of hepatocellular carcinoma after hepatectomy

BACKGROUND/AIMS We conducted a retrospective cohort study to investigate factors to early and late phase recurrence of hepatocellular carcinoma (HCC). METHODS The study population consisted of 249 patients including 157 with cirrhosis who underwent hepatectomy for HCC. The endpoint was time-to-recurrence. Using a Cox regression model, factors to early and late phase recurrences were investigated censoring recurrence-free patients at the 2-year time point and in patients without recurrence at 2 years. RESULTS Actuarial probability of overall recurrence at 1, 3, and 5 years were 0.301, 0.623, and 0.790, respectively, with a median follow-up of 624 days. Early recurrence was observed in 123 out of 249 patients; while late recurrence was found in 61 out of 113 patients. Factors to early recurrence were as follows: non-anatomical resection, presence of microscopic vascular invasion, and serum alpha-fetoprotein level >or=32 ng/ml. Those contributing to late phase recurrence were higher grade of hepatitis activity, multiple tumors, and gross tumor classification. CONCLUSIONS Variables associated with metastatic recurrence were factors to early phase recurrence; whereas those related with elevated carcinogenesis contributed to late phase recurrence, thus providing an epidemiological evidence that different mechanisms, i.e. metastasis and de novo, are involved in intrahepatic recurrence after hepatectomy for HCC.

Adoptive immunotherapy to lower postsurgical recurrence rates of hepatocellular carcinoma: a randomised trial

BACKGROUND Postsurgical recurrence of hepatocellular carcinoma (HCC) is frequent and fatal. Adoptive immunotherapy is active against HCC. We assessed whether postoperative immunotherapy could lower the frequency of recurrence. METHODS Between 1992 and 1995, we did a randomised trial in which 150 patients who had undergone curative resection for HCC were assigned adoptive immunotherapy (n=76) or no adjuvant treatment (n=74). Autologous lymphocytes activated vitro with recombinant interleukin-2 and antibody to CD3 were infused five times during the first 6 months. Primary endpoints were time to first recurrence and recurrence-free survival and analyses were by intention to treat. FINDINGS 76 patients received 370 (97%) of 380 scheduled lymphocyte infusions (mean cell number per patient 7.1x10(10) [SD 2.1]; CD3 and HLA-DR cells 78% [16]), and none had grade 3 or 4 adverse events. After a median follow-up of 4.4 years (range 0.2-6.7), adoptive immunotherapy decreased the frequency of recurrence by 18% compared with controls (45 [59%] vs 57 [77%]) [corrected] patients. Time to first recurrence in the immunotherapy group was significantly longer than that in the control group (48% [37-59] vs 33% [22-43] at 3 years, 38% [22-54] vs 22% [11-34] at 5 years; p=0.008). The immunotherapy group had significantly longer recurrence-free survival (p=0.01) and disease-specific survival (p=0.04) than the control group. Overall survival did not differ significantly between groups (p=0.09). INTERPRETATION Adoptive immunotherapy is a safe, feasible treatment that can lower recurrence and improve recurrence-free outcomes after surgery for HCC.

Extension of the Frontiers of Surgical Indications in the Treatment of Liver Metastases From Colorectal Cancer: Long-Term Results

OBJECTIVE To evaluate retrospectively the long-term results of an approach consisting of performing surgery in every patient in whom radical removal of all metastatic disease was technically feasible. SUMMARY BACKGROUND DATA The indications for surgical resection for liver metastases from colorectal cancer remain controversial. Several clinical risk factors have been reported to influence survival. METHODS Between March 1980 and December 1997, 235 patients underwent hepatic resection for metastatic colorectal cancer. Survival rates and disease-free survival as a function of clinical and pathologic determinants were examined retrospectively with univariate and multivariate analyses. RESULTS The overall 3-, 5-, 10-, and 15-year survival rates were 51%, 38%, 26%, and 24%, respectively. The stage of the primary tumor, lymph node metastasis, and multiple nodules were significantly associated with a poor prognosis in both univariate and multivariate analyses. Disease-free survival was significantly influenced by lymph node metastasis, a short interval between treatment of the primary and metastatic tumors, and a high preoperative level of carcinoembryonic antigen. The 10-year survival rate of patients with four or more nodules (29%) was better than that of patients with two or three nodules (16%), and similar to that of patients with a solitary lesion (32%). CONCLUSIONS Surgical resection is useful for treating liver metastases from colorectal cancer. Although multiple metastases significantly impaired the prognosis, the life expectancy of patients with four or more nodules mandates removal.

Prognostic impact of anatomic resection for hepatocellular carcinoma

Objectives:To evaluate the prognostic impact of anatomic versus nonanatomic resection on the patients’ survival after resection of a single hepatocellular carcinoma (HCC). Summary of Background Data:Anatomic resection is a reasonable treatment option for HCC; however, its clinical significance remains to be confirmed. Methods:Curative hepatic resection was performed for a single HCC in 210 patients; the patients were classified into the anatomic resection (n = 156) and nonanatomic resection (n = 54) groups. In 84 patients assigned to the anatomic resection group, segmentectomy or subsegmentectomy was performed. We evaluated the outcome of anatomic resection, including segmentectomy and subsegmentectomy, in comparison with that of nonanatomic resection, by the multivariate analysis taking into consideration 14 other clinical factors. Results:Both the 5-year overall survival and disease-free survival rates in the anatomic resection group were significantly better than those in the nonanatomic resection group (66% versus 35%, P = 0.01, and 34% versus 16%, P = 0.006, respectively). In the segmentectomy and subsegmentectomy group, the 5-year overall and disease-free survival rates were 67% and 28%, respectively, both of which were also higher than the corresponding rates in the nonanatomic resection group (P = 0.007 and P = 0.001, respectively). The results of multivariate analysis revealed that anatomic resection was a significantly favorable factor for overall and disease-free survivals: the hazard ratios were 0.57 (95% confidence interval, 0.32–0.99, P= 0.04), and 0.65 (0.43–0.96, P = 0.03). Conclusion:Anatomic resection for a single HCC yields more favorable results rather than nonanatomic resection.

Malignant transformation of adenomatous hyperplasia to hepatocellular carcinoma

To clarify the course of adenomatous hyperplasia (AH) of the liver, 17 patients with 20 biopsy-proven AH nodules were followed clinically for 1-5 years. At the initial biopsy the mean nodular diameter was 10 (SD 4) mm and the relative cellularity [( mean cellularity of AH divided by mean parenchymal cellularity] x 100) 141 (27). The criteria for diagnosis of malignant transformation of AH were both a doubling of nodular volume and changes on imaging. Between 6 and 50 months after biopsy, 9 of the 18 nodules which could still be accurately identified met the criteria for transformation; histological proof of hepatocellular carcinoma (HCC) was obtained later for 7 of these 9 nodules. The product of diameter and cellularity (transformation index) was the strongest predictor of the time to transformation. 9 AH nodules did not undergo transformation--7 did not meet one or both criteria and 2 became undetectable by imaging. Because of the high risk of malignant transformation, it can be concluded that AH is an absolute precursor of HCC. It should therefore be treated as a potential malignant disorder.

Selection Criteria for Repeat Hepatectomy in Patients With Recurrent Hepatocellular Carcinoma

Objective: The purpose of this study was to evaluate prognostic factors in patients with recurrence after curative resection of hepatocellular carcinoma (HCC) and to identify selection criteria for repeat resection. Summary Background Data: Recent studies have demonstrated that repeat hepatectomy is effective for treating intrahepatic recurrent HCC in selected patients. However, the prognostic factors in these patients have not been fully evaluated. Methods: From October 1994 to December 2000, 334 patients underwent primary resection for HCC, and 67 received a 2nd hepatectomy for recurrent HCC. The survival results in these 67 patients were analyzed, and prognostic factors were determined using 38 clinicopathological variables. The prognosis and operative risk in 11 and 6 patients who received a 3rd and 4th resection were also evaluated. Results: The overall 1-, 3-, and 5-year survival rates of the 334 patients after primary hepatectomy were 94%, 75%, and 56%, while those of the 67 patients after a 2nd resection were 93%, 70%, and 56%, respectively. There was no difference in survival (P = 0.64). All of the patients who underwent a 3rd or 4th are currently alive at a median follow-up of 2.5 and 1.4 years, respectively. The operative time and blood loss in the 2nd resection in patients who underwent a major primary resection were not different from those in patients who underwent minor hepatectomy at the 1st resection, and there were also no differences in these variables among the 2nd, 3rd, and 4th resections. In a multivariate analysis, absence of portal invasion at the 2nd resection (P = 0.01), single HCC at primary hepatectomy (P = 0.01), and a disease-free interval of 1 year or more after primary hepatectomy (P = 0.02) were independent prognostic factors after the 2nd resection. Twenty-nine patients with all 3 of these factors showed 3- and 5-year survival rates of 100% and 86%, respectively, after the 2nd resection. Conclusions: Repeat hepatic resection is the treatment of choice for patients who have previously undergone resection of a single HCC at the primary resection and in whom recurrence developed after a disease-free interval of 1 year or more and the recurrent tumor had no portal invasion.

Phase III study of sorafenib after transarterial chemoembolisation in Japanese and Korean patients with unresectable hepatocellular carcinoma

BACKGROUND In Japan and South Korea, transarterial chemoembolisation (TACE) is an important locoregional treatment for patients with unresectable hepatocellular carcinoma (HCC). Sorafenib, a multikinase inhibitor, has been shown effective and safe in patients with advanced HCC. This phase III trial assessed the efficacy and safety of sorafenib in Japanese and Korean patients with unresectable HCC who responded to TACE. METHODS Patients (n=458) with unresectable HCC, Child-Pugh class A cirrhosis and ≥25% tumour necrosis/shrinkage 1-3 months after 1 or 2 TACE sessions were randomised 1:1 to sorafenib 400mg bid or placebo and treated until progression/recurrence or unacceptable toxicity. Primary end-point was time to progression/recurrence (TTP). Secondary end-point was overall survival (OS). FINDINGS Baseline characteristics in the two groups were similar; >50% of patients started sorafenib>9 weeks after TACE. Median TTP in the sorafenib and placebo groups was 5.4 and 3.7 months, respectively (hazard ratio (HR), 0.87; 95% confidence interval (CI), 0.70-1.09; P=0.252). HR (sorafenib/placebo) for OS was 1.06 (95% CI, 0.69-1.64; P=0.790). Median daily dose of sorafenib was 386 mg, with 73% of patients having dose reductions and 91% having dose interruptions. Median administration of sorafenib and placebo was 17.1 and 20.1 weeks, respectively. No unexpected adverse events were observed. INTERPRETATION This trial, conducted prior to the reporting of registrational phase III trials, found that sorafenib did not significantly prolong TTP in patients who responded to TACE. This may have been due to delays in starting sorafenib after TACE and/or low daily sorafenib doses.

Long-term outcome of extended hemihepatectomy for hilar bile duct cancer with no mortality and high survival rate.

Objective To demonstrate our strategy for hilar bile duct cancer and to elucidate prognostic factors and the surgeons role in long-term survival. Summary Background Data Extended hemihepatectomy is recognized as a curative treatment of hilar bile duct cancer but is not always safe because of the risk of postoperative liver failure. A safe and beneficial strategy is required. Methods Fifty-eight consecutive major hepatectomies for hilar bile duct cancer were reviewed retrospectively. Appropriate preoperative treatments, biliary drainage, and portal embolization were performed before major hepatectomies. The short- and long-term results of our strategy are presented and analyzed. Results Biliary drainage and portal embolization were performed in 39 patients (67.2%) and 31 patients (53.4%), respectively. Major hepatectomies comprised 27 extended right and 22 extended left hemihepatectomies and 9 hepatoduodenopancreatectomies. Operative morbidity and mortality rates were 43% and 0%, respectively. There was no postoperative liver failure. The overall 5-year survival rate was 40%. Univariate analysis showed that residual tumor status, lymph node involvement, and perineural invasion were associated with patients’ long-term survival. A surgical margin over 5 mm resulted in better long-term survival. The delay resulting from preoperative treatment was not detrimental to long-term survival. Multivariate analysis showed that lymph node involvement was the only prognostic factor. Conclusions Our strategy, which includes preoperative biliary drainage and portal embolization, led to a reduction in the risks associated with major hepatectomy for hilar bile duct cancer, and resulted in zero mortality. Surgeons should aim at complete clearance of the tumor with an adequate surgical margin to ensure optimal long-term survival.

Predictive factors for postoperative recurrence of hepatocellular carcinoma

BACKGROUND/AIMS The survival rate for hepatocellular carcinoma after hepatectomy remains unsatisfactorily low because of the high recurrence rate. The purpose of this study was to elucidate predictive factors for postoperative recurrence of hepatocellular carcinoma. METHODS Univariate analysis and a multiple regression model were used to retrospectively determine the factors potentially related to recurrence in 98 patients with hepatocellular carcinoma who had undergone curative hepatic resection. RESULTS DNA diploidy, absence of alcohol abuse, and absence of vascular invasion were determined to be independent favorable predictive factors using a multivariate analysis with Coxs proportional hazards model. A predictive index was developed using these three factors according to the following equation: 1.486 x (O = DNA diploidy or 1 = DNA aneuploidy) + 1.138 x (O = absence or 1 = presence of alcohol abuse) + 0.946 x (O = absence or 1 = presence of vascular invasion). This index was used to classify the patients into two groups with good or poor prognosis. The median time for disease recurrence for the two groups was 24.1 and 9.2 months, respectively (P < 0.001). CONCLUSIONS The results may be useful in the determination of treatment strategies and postoperative follow-up schedules and in the design and analysis of future clinical trials of therapy for hepatocellular carcinoma.

Trans-ancestry mutational landscape of hepatocellular carcinoma genomes

Diverse epidemiological factors are associated with hepatocellular carcinoma (HCC) prevalence in different populations. However, the global landscape of the genetic changes in HCC genomes underpinning different epidemiological and ancestral backgrounds still remains uncharted. Here a collection of data from 503 liver cancer genomes from different populations uncovered 30 candidate driver genes and 11 core pathway modules. Furthermore, a collaboration of two large-scale cancer genome projects comparatively analyzed the trans-ancestry substitution signatures in 608 liver cancer cases and identified unique mutational signatures that predominantly contribute to Asian cases. This work elucidates previously unexplored ancestry-associated mutational processes in HCC development. A combination of hotspot TERT promoter mutation, TERT focal amplification and viral genome integration occurs in more than 68% of cases, implicating TERT as a central and ancestry-independent node of hepatocarcinogenesis. Newly identified alterations in genes encoding metabolic enzymes, chromatin remodelers and a high proportion of mTOR pathway activations offer potential therapeutic and diagnostic opportunities.