Jun Sakata

Bcl11b is required for differentiation and survival of αβ T lymphocytes

The gene Bcl11b, which encodes zinc finger proteins, and its paralog, Bcl11a, are associated with immune-system malignancies. We have generated Bcl11b-deficient mice that show a block at the CD4−CD8− double-negative stage of thymocyte development without any impairment in cells of B- or γδ T cell lineages. The Bcl11b−/− thymocytes showed unsuccessful recombination of Vβ to Dβ and lacked the pre–T cell receptor (TCR) complex on the cell surface, owing to the absence of Tcrb mRNA expression. In addition, we saw profound apoptosis in the thymus of neonatal Bcl11b−/− mice. These results suggest that Bcl11b is a key regulator of both differentiation and survival during thymocyte development.

Preoperative predictors of vascular invasion in hepatocellular carcinoma

AIMS Vascular invasion is an established adverse prognostic factor in hepatocellular carcinoma (HCC). The aim of the current study was to identify the preoperative predictors of vascular invasion in patients undergoing partial hepatectomy for HCC. METHODS A retrospective analysis of 227 consecutive patients who underwent partial hepatectomy for HCC was conducted. Vascular invasion was defined as gross or microscopic involvement of the vessels (portal vein or hepatic vein) within the peritumoral liver tissue. RESULTS Seventy-six (33%) patients had vascular invasion. Among the preoperative factors, only the tumour size (relative risk, 16.78; p<0.01) and the serum alpha-fetoprotein (AFP) level (relative risk, 3.57; p<0.01) independently predicted vascular invasion. As the tumour size increased, the incidence of vascular invasion increased: < or =2 cm, 3%; 2.1-3 cm, 20%; 3.1-5 cm, 38%; and > 5 cm, 65%. The incidence of vascular invasion was 32% in patients with serum AFP levels < or =1000 ng/mL, compared to 61% in patients with higher serum AFP levels (p<0.01). Patients with both tumours >5 cm and serum AFP levels >1000 ng/mL had an 82% incidence of vascular invasion. CONCLUSIONS The tumour size and serum AFP level, alone or in combination, are useful in predicting the presence or absence of vascular invasion before hepatectomy for HCC.

Risk of subsequent biliary malignancy in patients undergoing cyst excision for congenital choledochal cysts

The aim of this study was to elucidate the risk of subsequent biliary malignancy in patients undergoing cyst excision for congenital choledochal cysts.

Surgical Outcomes for Hepatocellular Carcinoma in Nonalcoholic Fatty Liver Disease

BackgroundThe present study investigated outcomes following surgical resection of hepatocellular carcinoma (HCC) in nonalcoholic fatty liver disease (NAFLD).MethodsPatients (n = 225) undergoing resection for HCC were divided into three groups: hepatitis C viral group (n = 147), hepatitis B viral group (n = 61), and NAFLD group (n = 17). Clinicopathological characteristics and surgical outcomes were analyzed retrospectively.ResultsPatients in the NAFLD group were older (P < 0.001), with a higher body mass index (P < 0.001) and larger tumors (P = 0.002) than patients who were positive for hepatitis viral markers. Eight patients in the NAFLD group were found to have nonalcoholic steatohepatitis (NASH) histologically. Postoperative morbidity and 30-day mortality rates were significantly higher in the NAFLD group (59% and 12%, respectively) than in the hepatitis C viral (31% and 0.7%, respectively) and hepatitis B viral (28% and 3.3%; P = 0.043 and P = 0.016, respectively) groups. All deaths in the NAFLD group were in patients with NASH-related cirrhosis who had undergone right hemihepatectomy. Survival after resection was comparable among the three groups (P = 0.391), but patients with NAFLD showed better disease-free survival on univariate (P = 0.048) and multivariate (P = 0.020) analyses.ConclusionsSurgical resection may provide a survival benefit for patients with NAFLD-related HCC. Patients with NASH-related cirrhosis undergoing major hepatic resection should be treated carefully.

Assessment of lymph node status in gallbladder cancer: location, number, or ratio of positive nodes

BackgroundAssessment of lymph node status is a critical issue in the surgical management of gallbladder cancer. The aim of this study was to compare the anatomical location of positive nodes, number of positive nodes, and lymph node ratio (LNR) as prognostic predictors in gallbladder cancer.MethodsWe conducted a retrospective analysis of 135 patients with gallbladder cancer who underwent a radical resection with regional lymphadenectomy. A total of 2,245 regional lymph nodes were retrieved (median, 14 per patient). The location of positive nodes was classified according to the AJCC staging manual (7th edition). ‘Optimal’ cutoff values were determined for the number of positive nodes and LNR based on maximal χ2 scores calculated with the Cox proportional hazards regression model.ResultsLymph node metastasis was found histologically in 59 (44%) patients. The ‘optimal’ cutoff values for the number of positive nodes and LNR were determined to be three nodes and 10%, respectively. Univariate analysis identified location of positive nodes (pN0, pN1, pN2; P < 0.001), number of positive nodes (0, 1 to 3, ≥4; P < 0.001), and LNR (0%, 0 to 10%, >10%; P < 0.001) as significant prognostic factors. Multivariate analysis identified number of positive nodes as an independent prognostic factor ( P = 0.004); however, location of positive nodes and LNR failed to remain as an independent variable.ConclusionsThe number of positive lymph nodes better predicts patient outcome after resection than either the location of positive lymph nodes or LNR in gallbladder cancer. Dividing the number of positive lymph nodes into three categories (0, 1 to 3, or ≥4) is valid for stratifying patients based on the prognosis after resection.

Preoperative cholangitis independently increases in-hospital mortality after combined major hepatic and bile duct resection for hilar cholangiocarcinoma

PurposeThis study evaluated the impact of ductal bile bacteria (bactibilia or cholangitis) on the development of surgical site infection (SSI) or in-hospital mortality after resection for hilar cholangiocarcinoma.Materials and methodsA retrospective analysis was conducted on 81 patients who underwent a combined major hepatic (hemihepatectomy or more extensive hepatectomy) and bile duct resection for hilar cholangiocarcinoma. Ductal bile was submitted for bacterial culture before or during the operation.ResultsThe incidence of SSI was higher in patients with preoperative bactibilia (83%) than in patients without (52%; P = 0.008). Preoperative bactibilia was an independent variable associated with SSI (relative risk 9.003; P = 0.002). The incidence of in-hospital mortality was higher in patients with preoperative cholangitis (33%) than in patients without (6%; P = 0.009). Preoperative cholangitis was the only independent variable associated with in-hospital mortality (relative risk 9.115; P = 0.006).ConclusionsPreoperative cholangitis independently increases in-hospital mortality after combined major hepatic and bile duct resection for hilar cholangiocarcinoma, whereas preoperative bactibilia independently increases SSI.

Overexpression of osteopontin independently correlates with vascular invasion and poor prognosis in patients with hepatocellular carcinoma.

This study retrospectively evaluated the immunohistochemical expression of 3 cell adhesion molecules (CAMs), E-cadherin, beta-catenin, and osteopontin, according to tumor grade in 125 surgically resected specimens of hepatocellular carcinoma (HCC). The aims of this study were to identify factors associated with vascular invasion and to elucidate the prognostic value of CAMs. The median follow-up time was 110 months. The levels of E-cadherin, beta-catenin, and osteopontin immunoreactivity were significantly associated with Edmondson-Steiner grade but not with tumor size. There was increased loss of E-cadherin, nonnuclear overexpression of beta-catenin, and overexpression of osteopontin in tumors of higher histologic grade. Vascular invasion was found in 44 (35%) of 125 resected specimens. Logistic regression analysis identified 3 tumor-related factors that were independently associated with vascular invasion-tumor size more than 3 cm, Edmondson-Steiner grades III to IV, and overexpression of osteopontin. Among the tested CAMs, osteopontin (P = .0110) and E-cadherin (P = .0287) were significant prognostic factors by univariate analysis. The Cox proportional hazard regression analysis revealed that Edmondson-Steiner grades III to IV (relative risk [RR], 3.028; P < .001), the presence of vascular invasion (RR, 1.964; P = .011), overexpression of osteopontin (RR, 1.755; P = .034), serum alpha-fetoprotein level more than 20 ng/mL (RR, 1.834; P = .037), and Child-Pugh classification B to C (RR, 1.880; P = .040) were found to be independently significant factors associated with survival after hepatectomy. These results suggest that overexpression of osteopontin independently correlates with vascular invasion and thus predicts poor survival for patients with HCC, whereas aberrant expression of E-cadherin or beta-catenin does not.

Mode of hepatic spread from gallbladder carcinoma: an immunohistochemical analysis of 42 hepatectomized specimens.

This study aimed to clarify the mode of hepatic spread from gallbladder carcinoma and to elucidate its prognostic value. A retrospective analysis was conducted of 42 consecutive patients who underwent resection for gallbladder carcinoma with hepatic involvement verified histologically. The mode of hepatic spread was classified into 3 patterns: direct invasion through the gallbladder bed, portal tract invasion, and hepatic metastatic nodules. Intrahepatic lymphatic invasion was declared when either single tumor cells or cell clusters were clearly visible within vessels that showed immunoreactivity to the D2-40 monoclonal antibody. Seven, 24, and 11 patients had direct invasion alone, portal tract invasion with (22 patients) or without (2 patients) direct invasion, and hepatic metastatic nodules, respectively. Of the 24 patients with portal tract invasion, 14 had intrahepatic lymphatic invasion, 8 had neither intrahepatic lymphatic nor venous invasion, and 2 had both intrahepatic lymphatic and venous invasion. To date, 4 patients with direct invasion alone and 4 patients with portal tract invasion survived more than 5 years after resection, whereas all the patients with hepatic metastatic nodules died within 11 months after resection, irrespective of the type of hepatectomy. The mode of hepatic spread (P<0.001) was a strong independent prognostic factor. Direct liver invasion and portal tract invasion, which features intrahepatic lymphatic invasion, are the main modes of hepatic spread from resectable gallbladder carcinoma. The mode of hepatic spread independently predicts long-term survival after resection for patients with gallbladder carcinoma. Hepatic metastatic nodules indicate a dismal outcome after resection.

Genomic landscape of colorectal cancer in Japan: Clinical implications of comprehensive genomic sequencing for precision medicine

BackgroundComprehensive genomic sequencing (CGS) has the potential to revolutionize precision medicine for cancer patients across the globe. However, to date large-scale genomic sequencing of cancer patients has been limited to Western populations. In order to understand possible ethnic and geographic differences and to explore the broader application of CGS to other populations, we sequenced a panel of 415 important cancer genes to characterize clinically actionable genomic driver events in 201 Japanese patients with colorectal cancer (CRC).MethodsUsing next-generation sequencing methods, we examined all exons of 415 known cancer genes in Japanese CRC patients (n = 201) and evaluated for concordance among independent data obtained from US patients with CRC (n = 108) and from The Cancer Genome Atlas-CRC whole exome sequencing (WES) database (n = 224). Mutation data from non-hypermutated Japanese CRC patients were extracted and clustered by gene mutation patterns. Two different sets of genes from the 415-gene panel were used for clustering: 61 genes with frequent alteration in CRC and 26 genes that are clinically actionable in CRC.ResultsThe 415-gene panel is able to identify all of the critical mutations in tumor samples as well as WES, including identifying hypermutated tumors. Although the overall mutation spectrum of the Japanese patients is similar to that of the Western population, we found significant differences in the frequencies of mutations in ERBB2 and BRAF. We show that the 415-gene panel identifies a number of clinically actionable mutations in KRAS, NRAS, and BRAF that are not detected by hot-spot testing. We also discovered that 26% of cases have mutations in genes involved in DNA double-strand break repair pathway. Unsupervised clustering revealed that a panel of 26 genes can be used to classify the patients into eight different categories, each of which can optimally be treated with a particular combination therapy.ConclusionsUse of a panel of 415 genes can reliably identify all of the critical mutations in CRC patients and this information of CGS can be used to determine the most optimal treatment for patients of all ethnicities.

Interstitial pneumonia arising in a patient treated with oxaliplatin, 5-fluorouracil, and, leucovorin (FOLFOX)

Information concerning the pulmonary toxicity of oxaliplatin with infusional 5-fluorouracil plus leucovorin (FOLFOX) is very limited. We herein report the case of a patient with FOLFOX-induced interstitial pneumonia. An 82-year-old man with unresectable colon cancer liver metastases was referred to our department for chemotherapy with the FOLFOX protocol. After the administration of ten cycles, he visited our outpatient clinic with a 2-week history of coughing and shortness of breath; he was afebrile. A chest radiograph showed reticular shadows with ground-glass opacities mainly involving the middle and lower zones of the right lung. Computed tomography depicted ground-glass opacities with superimposed reticulation in the right lung. A diagnosis of FOLFOX-induced interstitial pneumonia was made based on the clinical course and imaging findings. The symptoms disappeared within 3 days after the cessation of the FOLFOX regimen and the initiation of high-dose corticosteroid treatment. Two months after the initiation of the corticosteroid treatment, complete remission of the radiological abnormalities was confirmed; thereafter, interstitial pneumonia did not recur despite the reintroduction of 5-fluorouracil/leucovorin alone, suggesting that 5-fluorouracil/leucovorin alone was not responsible for the development of the interstitial pneumonia. Thus, oxaliplatin, alone or in combination with 5-fluorouracil/leucovorin, may have caused the interstitial pneumonia in this patient. Once interstitial pneumonia has occurred, cessation of the regimen is mandatory, and high-dose corticosteroid treatment is commonly given to rescue patients from this potentially lethal complication.