Tomoo Kosuge

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.

Whole-genome sequencing of liver cancers identifies etiological influences on mutation patterns and recurrent mutations in chromatin regulators

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. We sequenced and analyzed the whole genomes of 27 HCCs, 25 of which were associated with hepatitis B or C virus infections, including two sets of multicentric tumors. Although no common somatic mutations were identified in the multicentric tumor pairs, their whole-genome substitution patterns were similar, suggesting that these tumors developed from independent mutations, although their shared etiological backgrounds may have strongly influenced their somatic mutation patterns. Statistical and functional analyses yielded a list of recurrently mutated genes. Multiple chromatin regulators, including ARID1A, ARID1B, ARID2, MLL and MLL3, were mutated in ∼50% of the tumors. Hepatitis B virus genome integration in the TERT locus was frequently observed in a high clonal proportion. Our whole-genome sequencing analysis of HCCs identified the influence of etiological background on somatic mutation patterns and subsequent carcinogenesis, as well as recurrent mutations in chromatin regulators in HCCs.

Prevalence of FOXP3 + Regulatory T Cells Increases During the Progression of Pancreatic Ductal Adenocarcinoma and Its Premalignant Lesions

Purpose: Antitumor immune response changes drastically during the progression of cancers. Established cancers often escape from the host immune system, although specific immune surveillance operates in the early stages of tumorigenesis in murine models. CD4+CD25+ regulatory T cells (TR) play a central role in self-tolerance and suppress effective antitumor immune responses. The aim of this study was to investigate the clinical significance and roles of TR in the progression and multistep carcinogenesis of pancreatic ductal adenocarcinoma. Experimental Design: We raised anti-FOXP3 antibodies and used them in immunohistochemical studies of the prevalence of FOXP3+CD4+CD25+ TR in the CD4+ T cells, which infiltrated in tissue and draining lymph nodes of 198 pancreatic ductal adenocarcinomas, their premalignant lesions (84 lesions of pancreatic intraepithelial neoplasias and 51 intraductal papillary-mucinous neoplasms), and 15 nonneoplastic pancreatic lesions. Results: The prevalence of TR was significantly increased in the ductal adenocarcinomas compared with that in the stroma of nonneoplastic inflammation (P < 0.0001). The increased prevalence of TR was significantly correlated with certain clinicopathologic factors. A better prognosis was observed in patients with a low prevalence of TR, and this was independent of other survival factors (P < 0.0001). Infiltration of intraepithelial CD8+TIA-1+ cytotoxic T cells in pancreatic ducts was marked in low-grade premalignant lesions but diminished during the progression of both pancreatic intraepithelial neoplasias and intraductal papillary-mucinous neoplasms. Conversely, the prevalence of TR increased significantly during the progression of premalignant lesions. Conclusions: TR play a role in controlling the immune response against pancreatic ductal carcinoma from the premalignant stage to established cancer. In pancreatic ductal carcinoma, a high prevalence of TR seems to be a marker of poor prognosis.

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.

FOXP3+ regulatory T cells affect the development and progression of hepatocarcinogenesis

Purpose: Tumor-infiltrating lymphocytes represent the host immune response to cancer. CD4+CD25+FOXP3+ regulatory T cells (Tregs) suppress the immune reaction. The aim of the present study was to investigate the clinicopathologic significance and roles of Tregs and CD8+ T cells during hepatocarcinogenesis. Experimental Design: We examined the infiltration of FOXP3+ Tregs and CD8+ T cells in the tumor stroma and nontumorous liver parenchyma using 323 hepatic nodules including precursor lesions, early hepatocellular carcinoma (HCC), and advanced HCC, along with 39 intrahepatic cholangiocarcinomas and 59 metastatic liver adenocarcinomas. We did immunohistochemical comparative studies. Results: The prevalence of Tregs was significantly higher in HCC than in the nontumorous liver (P < 0.001). The patient group with a high prevalence of Tregs infiltrating HCC showed a significantly lower survival rate (P = 0.007). Multivariate analysis revealed that the prevalence of Tregs infiltrating HCC was an independent prognostic factor. The prevalence of Tregs increased in a stepwise manner (P < 0.001) and that of CD8+ T cells decreased during the progression of hepatocarcinogenesis (P < 0.001). Regardless of the presence of hepatitis virus infection or histopathologic evidence of hepatitis, the prevalence of Tregs was significantly increased in nontumorous liver bearing primary hepatic tumors. Conclusions: Tregs play a role in controlling the immune response to HCC during the progression of hepatocarcinogenesis. It has been suggested that primary hepatic cancers develop in liver that is immunosuppressed by a marked infiltration of Tregs. A high prevalence of Tregs infiltrating HCC is thought to be an unfavorable prognostic indicator.

Improved surgical results for hilar cholangiocarcinoma with procedures including major hepatic resection.

OBJECTIVE To evaluate the long-term outcome of aggressive surgery incorporating hepatic resection and systematic nodal dissection for advanced carcinoma involving the hepatic hilus. SUMMARY BACKGROUND DATA Few long-term results are available regarding radical surgery incorporating major hepatectomy and nodal dissection. METHODS A retrospective analysis was undertaken in 107 patients with carcinoma involving the hepatic hilus treated between 1980 and 1997. Resectional surgery was performed in 65 patients, 52 of whom underwent major hepatectomies. The effects of clinical and pathologic factors were assessed by univariate and multivariate analyses. RESULTS Sixty percent of the patients with resectional surgery had stage IVA or IVB disease, and 92.3% of them underwent major hepatectomies. No in-hospital deaths were encountered in the 35 most recent resections, whereas there were six deaths in the early period. Resectional surgery was associated with a survival benefit, especially when resection margins were free from cancerous infiltration. The estimated 5-year survival rate after resection, including all deaths, was 34.8%; this was 51.6% when the margins were clear. Nodal involvement was documented in 44.6% of the resections. However, patients with metastases limited to the regional nodes showed a survival rate similar to that in patients without nodal involvement. Significant predictive factors for survival after resection were extension to the gallbladder, nodal status, resectional margins, histologic type, and gender. CONCLUSIONS The combination of major hepatectomy with systematic nodal dissection gave a good chance of prolonged survival for patients with carcinoma involving the hepatic hilus, even when the disease was advanced. Less-extensive procedures were also beneficial for less-advanced disease if clear resectional margins were secured.

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.

A randomised phase III trial comparing gemcitabine with surgery-only in patients with resected pancreatic cancer: Japanese Study Group of Adjuvant Therapy for Pancreatic Cancer

Background:This multicentre randomised phase III trial was designed to determine whether adjuvant chemotherapy with gemcitabine improves the outcomes of patients with resected pancreatic cancer.Methods:Eligibility criteria included macroscopically curative resection of invasive ductal carcinoma of the pancreas and no earlier radiation or chemotherapy. Patients were randomly assigned at a 1 : 1 ratio to either the gemcitabine group or the surgery-only group. Patients assigned to the gemcitabine group received gemcitabine at a dose of 1000 mg m−2 over 30 min on days 1, 8 and 15, every 4 weeks for 3 cycles.Results:Between April 2002 and March 2005, 119 patients were enrolled in this study. Among them, 118 were eligible and analysable (58 in the gemcitabine group and 60 in the surgery-only group). Both groups were well balanced in terms of baseline characteristics. Although heamatological toxicity was frequently observed in the gemcitabine group, most toxicities were transient, and grade 3 or 4 non-heamatological toxicity was rare. Patients in the gemcitabine group showed significantly longer disease-free survival (DFS) than those in the surgery-only group (median DFS, 11.4versus 5.0 months; hazard ratio=0.60 (95% confidence interval (CI): 0.40–0.89); P=0.01), although overall survival did not differ significantly between the gemcitabine and surgery-only groups (median overall survival, 22.3 versus 18.4 months; hazard ratio=0.77 (95% CI: 0.51–1.14); P=0.19).Conclusion:The current results suggest that adjuvant gemcitabine contributes to prolonged DFS in patients undergoing macroscopically curative resection of pancreatic cancer.

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.