TAS2940, a novel brain-penetrable pan-ERBB inhibitor, for tumors with HER2 and EGFR aberrations.

Genetic alterations in human epidermal growth factor receptor type 2 (HER2)/epidermal growth factor receptor (EGFR) are commonly associated with breast and lung cancers and glioblastomas. Cancers with avian erythroblastosis oncogene B (ERBB) deregulation are highly metastatic and can cause primary brain tumors. Currently, no pan-ERBB inhibitor with remarkable brain penetration is available. Here, TAS2940, a novel irreversible pan-ERBB inhibitor with improved brain penetrability, was evaluated for its efficacy against several ERBB aberrant cancer models. The selectivity of TAS2940 was evaluated by enzymatic kinase assays. The inhibitory effects of TAS2940 against ERBB genetic alterations were examined using MCF10A cells expressing various HER2 or EGFR mutations and other generic cell lines harboring deregulated ERBB expression. In vivo efficacy of TAS2940 was examined following oral treatment in subcutaneous or intracranial xenograft cancer models. TAS2940 was highly potent against cells harboring HER2/EGFR alterations. TAS2940 could selectively inhibit phosphorylation of targets and the growth of cancer cells with ERBB aberrations in vitro. TAS2940 also inhibited tumor growth in xenograft mouse models with ERBB aberrations: HER2 amplification, HER2/EGFR exon 20 insertions, and EGFR vIII mutation. TAS2940 was effective in the intracranial xenograft models of HER2/EGFR cancers and improved the survival of these mice. TAS2940 has promising therapeutic effects in preclinical study against cancers harboring HER2/EGFR mutations, especially metastatic and primary brain tumors. Our results highlight potential novel strategies against lung cancers with brain metastases harboring HER2/EGFR exon 20 insertions and glioblastomas with EGFR aberrations.

VAX014, an Oncolytic Therapy, Reduces Adenomas and Modifies Colon Microenvironment in Mouse Model of CRC.

Colorectal cancer (CRC) remains the third most common form of cancer and, despite its reduced mortality, results in over 50,000 deaths annually, highlighting the need for novel therapeutic approaches. VAX014 is a novel clinical-stage, oncolytic bacterial minicell-based therapy shown to elicit protective antitumor immune responses in cancer, but it has not been fully evaluated in CRC. Here, VAX014 was demonstrated to induce oncolysis in CRC cell lines in vitro and was evaluated in vivo, both as a prophylactic (before spontaneous development of adenomatous polyps) and as a neoadjuvant treatment using the Fabp-CreXApcfl468 preclinical animal model of colon cancer. As a prophylactic, VAX014 significantly reduced the size and number of adenomas without inducing long term changes in the gene expression of inflammatory, T helper 1 antitumor, and immunosuppression markers. In the presence of adenomas, a neoadjuvant VAX014 treatment reduced the number of tumors, induced the gene expression of antitumor TH1 immune markers in adenomas, and promoted the expansion of the probiotic bacterium Akkermansia muciniphila. The neoadjuvant VAX014 treatment was associated with decreased Ki67 proliferation in vivo, suggesting that VAX014 inhibits adenoma development through both oncolytic and immunotherapeutic effects. Combined, these data support the potential of VAX014 treatment in CRC and "at risk" polyp-bearing or early adenocarcinoma populations.

Validity of the Algorithm for Liver Resection of Hepatocellular Carcinoma in the Caudate Lobe.

BACKGROUND: We aimed to validate our algorithm for resecting Hepatocellular carcinoma (HCC) in the caudate lobe based on tumor location, tumor size, and indocyanine green clearance rate. METHODS: Patients who underwent curative resections for solitary HCC in the caudate lobe were included. The surgical outcomes of patients with HCC in the caudate lobe were compared with those of patients with HCC in other sites of the liver. RESULTS: After one-to-one matching, the caudate-lobe group (n = 150) had longer operation time, greater amount of bleeding, lower weight of resected specimens, and shorter distance between tumor and resection line than the other-sites group (n = 150), but the complication rates were not different between the groups (38.0% vs. 34.1%, P = 0.719). After a median follow-up period of 3.0 years (range, 0.3-16.2 years), the median overall survivals were 6.5 (95% confidence interval [CI], 5.3-7.9) and 7.5 years (95% CI, 6.3-9.7) in the caudate-lobe and other-site groups, respectively (P = 0.430). Median recurrence-free survivals in the caudate-lobe group (1.9 years; 95% CI, 1.4-2.7) had a tendency to be shorter than those in the other-sites group (2.3 years; 1.7-3.4) (P = 0.052). CONCLUSIONS: Patients' survival and complication rates in the caudate-lobe group were comparable to those in the other-sites group; therefore, our algorithm for resecting HCC in the caudate lobe is of clinical use.

Enhanced Retrieval of Taste Associative Memory by Chemogenetic Activation of Locus Coeruleus Norepinephrine Neurons.

The ability of animals to retrieve memories stored in response to the environment is essential for behavioral adaptation. Norepinephrine (NE)-containing neurons in the brain play a key role in the modulation of synaptic plasticity underlying various processes of memory formation. However, the role of the central NE system in memory retrieval remains unclear. Here, we developed a novel chemogenetic activation strategy exploiting insect olfactory ionotropic receptors (IRs), termed "IR-mediated neuronal activation," and used it for selective stimulation of NE neurons in the locus coeruleus (LC). Drosophila melanogaster IR84a and IR8a subunits were expressed in LC NE neurons in transgenic mice. Application of phenylacetic acid (a specific ligand for the IR84a/IR8a complex) at appropriate doses induced excitatory responses of NE neurons expressing the receptors in both slice preparations and in vivo electrophysiological conditions, resulting in a marked increase of NE release in the LC nerve terminal regions (male and female). Ligand-induced activation of LC NE neurons enhanced the retrieval process of conditioned taste aversion without affecting taste sensitivity, general arousal state, and locomotor activity. This enhancing effect on taste memory retrieval was mediated, in part, through α1- and ß-adrenergic receptors in the basolateral nucleus of the amygdala (BLA; male). Pharmacological inhibition of LC NE neurons confirmed the facilitative role of these neurons in memory retrieval via adrenergic receptors in the BLA (male). Our findings indicate that the LC NE system, through projections to the BLA, controls the retrieval process of taste associative memory.SIGNIFICANCE STATEMENT Norepinephrine (NE)-containing neurons in the brain play a key role in the modulation of synaptic plasticity underlying various processes of memory formation, but the role of the NE system in memory retrieval remains unclear. We developed a chemogenetic activation system based on insect olfactory ionotropic receptors and used it for selective stimulation of NE neurons in the locus coeruleus (LC) in transgenic mice. Ligand-induced activation of LC NE neurons enhanced the retrieval of conditioned taste aversion, which was mediated, in part, through adrenoceptors in the basolateral amygdala. Pharmacological blockade of LC activity confirmed the facilitative role of these neurons in memory retrieval. Our findings indicate that the LC-amygdala pathway plays an important role in the recall of taste associative memory.

Dysfunction of Cl- channels promotes epithelial to mesenchymal transition in oral squamous cell carcinoma via activation of Wnt/ß-catenin signaling pathway.

Oral squamous cell carcinoma (OSCC) is a highly aggressive carcinoma with a high incidence of recurrence and distant metastasis. However, the mechanism of epithelial to mesenchymal transition (EMT) during tumor progression and metastasis in OSCC has not yet been fully elucidated. It is well known that the Cl- channel controls cell volume and activates several signaling pathways for cell differentiation. The aim of the present study was to investigate the role of the Cl- channel on EMT in the OSC 20 cell line, which is an OSCC line. OSC-20 cells were cultured with low serum medium containing a Cl- channel blocker NPPB. Morphological changes, gene expression, immunoreactivity, cell volume, and signaling pathway of the NPPB-treated OSC-20 cells were evaluated. The NPPB-treated OSC-20 cells showed typical morphology of mesenchymal cells. The expression levels of the epithelial marker E-cadherin in the NPPB-treated OSC-20 cells were lower than those of the untreated and TGF-ß1-treated OSC-20 cells. On the other hand, mesenchymal markers such as vimentin, ZEB1, and Snail, in the NPPB-treated OSC-20 cells were higher than those in the untreated and TGF-ß1-treated OSC-20 cells. Furthermore, a large number of vimentin-positive cells also appeared in the NPPB-treated OSC-20 cells. Additionally, the cell volume of these cells was significantly increased compared to that of the untreated and TGF-ß1-treated cells. Interestingly, NPPB did not activate the TGF-ß/smad signaling pathway, but activated the Wnt/ß-catenin signaling pathway. These results suggest that Cl- channel dysfunction promoted EMT via activation of the Wnt/ß-catenin signaling pathway in OSCC.

Favorable outcomes of surgical resection for extrahepatic recurrent hepatocellular carcinoma.

AIM: Repeat resection for intrahepatic recurrent hepatocellular carcinoma (HCC) is effective for the long-term survival of patients; however, little is known about the surgical outcomes of extrahepatic nodules. The aim of this study is to investigate whether resection can contribute to the survival of patients with extrahepatic recurrent HCC. METHODS: Under the conditions that intrahepatic recurrent HCC was absent or controlled by locoregional therapies, patients who had resectable extrahepatic recurrent HCC in the lymph nodes, adrenal gland, peritoneum, lung, or brain were included in this study. The survival of patients who did (Surgical group) and did not (Non-surgical group, underwent other therapies) undergo resection for extrahepatic recurrent HCC was compared. RESULTS: Thirty-eight and 26 patients were included in the Surgical and Non-surgical groups, respectively. No patient had severe postoperative complications. After a median follow-up of 1.2 (range, 0.2-8.8) years, the median cumulative incidence of extrahepatic recurrent HCC was 1.2 years (95% confidence interval [CI], 0.4-3.5) in the Surgical group. The median overall survival was 5.3 (95% CI, 2.5-8.8) and 1.1 (0.8-2.3) years in the Surgical and Non-surgical groups, respectively (P < 0.001). The 5-year rates of survival were 60.5% and 9.1% in the Surgical and Non-surgical groups, respectively. Surgical resection, α-fetoprotein, disease-free interval, and metastasis at the adrenal gland were the independent factors for overall survival. CONCLUSIONS: Due to the favorable surgical outcomes, resection should be considered as one of the therapeutic choices for patients with extrahepatic recurrent HCC if intrahepatic recurrent HCC can be controlled by locoregional therapies.

Liver Resection Versus Embolization for Recurrent Hepatocellular Carcinoma.

BACKGROUND: Despite curative resection, hepatocellular carcinoma (HCC) has a high probability of recurrence. We validated the potential role of liver resection (LR) for recurrent HCC. METHODS: Patients with intrahepatic recurrence with up to three lesions were included. We compared survival times of patients undergoing their first LR to those of patients undergoing repeated LR. Then, survival times of the patients who had undergone LR and transcatheter chemoembolization (TACE) for recurrent HCC after propensity score matching were compared. RESULTS: After a median follow-up period of 3.1 years (range, 0.2-16.3), median overall survival times were 6.5 years (95% CI 6.0-7.0), 5.7 years (5.2-6.2), and 5.1 years (4.9-7.3) for the first LR (n = 1234), second LR (n = 273), and third LR (n = 90) groups, respectively. Severe complications frequently occurred in the first LR group (p = 0.059). Operative times were significantly longer for the third LR group (p = 0.012). After the first recurrence, median survival times after one-to-one pair matching were 5.7 years (95% CI 4.5-6.5) and 3.1 years (2.1-3.8) for the second LR group (n = 146) and TACE group (n = 146), respectively (p < 0.001). The median survival time of the third LR group (n = 41) (6.2 years; 95% CI 3.7-NA) was also longer than that of TACE group (n = 41) (3.4 years; 1.8-4.5; p = 0.010) after the second recurrence. CONCLUSIONS: Repeated LR for recurrent HCC is the procedure of choice if there are three or fewer tumors.

Activity of TAS4464, a novel NEDD8 activating enzyme E1 inhibitor, against multiple myeloma via inactivation of nuclear factor κB pathways.

The ubiquitin proteasome pathway is essential for the proliferation and survival of multiple myeloma (MM) cells. TAS4464, a novel highly potent inhibitor of NEDD8 activating enzyme, selectively inactivates cullin-RING ubiquitin E3 ligases, resulting in accumulation of their substrates. Here, we examined 14 MM cell lines treated with TAS4464. TAS4464 induced growth arrest and cell death in the MM cell lines even in the presence of bone marrow stromal cells. It also induced the accumulation of phospho-inhibitor of κBα and phospho-p100, impaired the activities of nuclear factor κB (NF-κB) transcription factors p65 and RelB, and decreased the expression of NF-κB target genes, suggesting that TAS4464 inhibits both the canonical and non-canonical NF-κB pathways. TAS4464 had similar effects in an in vivo human-MM xenograft mouse model in which it was also observed to have strong antitumor effects. TAS4464 synergistically enhanced the antitumor activities of the standard MM chemotherapies bortezomib, lenalidomide/dexamethasone, daratumumab and elotuzumab. Together, these results suggest that the anti-MM activity of TAS4464 occurs via inhibition of the NF-κB pathways, and that treatment with TAS4464 is a potential approach for treating MM by single and combination therapies.

Prediction of esophageal varices by liver and spleen MR elastography.

OBJECTIVES: We aimed to assess the diagnostic performance of MR elastography (MRE) in predicting esophageal varices (EVs) in patients with chronic liver disease. METHODS: We prospectively performed liver (LSM) and spleen stiffness measurements (SSM) using MRE and endoscopic screening for EVs to determine if patients with hepatocellular carcinoma were eligible for resection. We investigated whether LSM, SSM, and other non-invasive preoperative parameters were associated with the presence of EVs. In order to predict EVs, 211 patients were divided into training (n = 140) and test (n = 71) groups. A nomogram was built using independent factors based on logistic regression analysis in the training group and its accuracy was validated using an independent cohort. RESULTS: Forty-six patients (21.8%) were diagnosed as having EVs (mild, n = 36; severe, n = 10). According to multiple regression analysis, LSM (odds ratio, 2.362; 95% confidence interval [CI], 1.341-4.923; p = 0.001) and SSM (1.489; 1.095-2.235; p = 0.010) were independent predictors of EVs in the training group. The nomogram showed good discrimination, with a C-index of 0.942 (95% CI, 0.892-0.974) through internal validation, and good calibration. Application of the nomogram in the test group still gave good discrimination (C-index, 0.948; 95% CI, 0.868-0.995). CONCLUSIONS: The combination of LSM and SSM using MRE is an accurate tool to identify patients at risk for EVs. KEY POINTS: • Performance of MR elastography can estimate the presence of esophageal varices non-invasively. • Liver and spleen stiffness measurements are independent predictors for esophageal varices. • The nomogram using a combination of liver and spleen stiffness measurements allows for the risk of esophageal varices.

Liver resection for recurrent hepatocellular carcinoma after radiofrequency ablation therapy.

AIM: Although radiofrequency ablation (RFA) is an effective local treatment of hepatocellular carcinoma (HCC), local recurrence is relatively frequent. We aimed to elucidate the validity of salvage liver resection for recurrent HCC after RFA. METHODS: Patients who underwent liver resection for recurrent HCC after RFA (LR after RFA) and those who underwent second liver resection for recurrent HCC (second LR) were included. The short-term outcomes were compared between the two groups. The survival rates between the two groups were compared after propensity-score matching to adjust for the variables, including patient background, liver function, and tumor status. RESULTS: Major resection was frequently carried out in the LR after RFA group, but there was no significant difference both in operative data and complication rate between LR after RFA (n = 54) and second LR (n = 266) groups. After a median follow-up period of 1.8 years (range, 0.2-10.5), the median overall survival was 4.4 years (95% confidence interval [CI], 2.2 - not applicable) and 5.6 years (95% CI, 4.5-7.3; P = 0.023) in the LR after RFA group (n = 54) and second LR group (n = 54), respectively, and recurrence-free survival was 1.3 years (0.4-2.2) and 1.2 years (0.5-1.8, P = 0.469), respectively. The only independent factor for overall survival of the LR after RFA group was local recurrence (hazard ratio, 2.73; 1.06-9.00). CONCLUSIONS: Salvage liver resection of recurrent HCC after RFA could be recommended due to the safety of the procedure, especially in patients without local tumor progression after RFA.

[Machine Learning Applications in Cancer Genome Medicine].

Practical cancer genome medicine requires large-scale data analysis for many types of biological data such as cancer driver mutations, aberrantly methylated regions, gene expression also biological knowledge from literature. Machine learning algorithms play an important role in bioinformatics of clinical oncology. In this review, we examine the applications of machine learning algorithm on recent research of cancer genome medicine. As an introduction, we consider relationship between artificial intelligence(AI)and machine learning and characterize the technical advantages of deep learning. The later part of this article examines 4 research publications within 3 domains. That includes comprehensive research about actionable mutations, novel approach for identifying activated Ras pathway and feasible methodologies to increase sensitivity of detecting cancer with cell-free DNA from 2 different research groups.

Diabetes mellitus not an unfavorable factor on the prognosis of hepatitis C virus-related hepatocellular carcinoma.

AIM: Diabetes mellitus (DM) is a potential risk factor for hepatocarcinogenesis, especially in patients with hepatitis C virus (HCV) infection. We aimed to elucidate whether DM influences the surgical outcomes of patients with hepatocellular carcinoma (HCC). METHODS: Our patients were routinely controlled to keep urinary glucose excretion to less than 3.0 g/day before surgery, and the serum glucose level under 200 mg/dL after surgery. The surgical outcomes and postoperative complications of 112 patients with HCV-related HCC with DM (DM group) were compared to those of 112 propensity-matched patients without DM (non-DM group). RESULTS: After a median follow-up of 3.2 years (range, 0.2-11.3 years), the median overall (5.2 years; 95% confidence interval, 3.8-6.5 years) and recurrence-free survival (2.2 years; 1.7-2.9 years) in the DM group were not significantly different from those (6.3 years; 5.4-7.1 years, P = 0.337; and 2.2 years; 1.7-3.6 years, P = 0.613) in the non-DM group. The independent factors related to overall survival were the background liver (hazard ratio, 2.06; 95% confidence interval, 1.27-3.39, P = 0.014) and tumor differentiation grade (2.07; 1.14-4.05, P = 0.015). Thirty-two patients (28.5%) in the DM group and 32 patients (28.5%) in the non-DM group had morbidities after operation, with no significant difference between the groups (P = 1.000). Furthermore, postoperative control status of DM did not affect the prognostic outcome. CONCLUSION: Diabetes mellitus does not affect the surgical outcomes of patients with HCV-related HCC, and it is not an unfavorable factor when selecting candidates for liver resection of HCC.

Synthesis of Chiral Tritylpyrrolidine Derivatives and Their Application to Asymmetric Benzoyloxylation.

An efficient synthesis of novel chiral tritylpyrrolidine derivatives has been developed. Single stereoisomers of various tritylpyrrolidine derivatives can be readily obtained through diastereomer separation by simple silica gel column chromatography. Representative compounds of this class have been shown to be efficient amine organocatalysts for asymmetric benzoyloxylation.

A prediction model for the grade of liver fibrosis using magnetic resonance elastography.

BACKGROUND: Liver stiffness measurement (LSM) has recently become available for assessment of liver fibrosis. We aimed to develop a prediction model for liver fibrosis using clinical variables, including LSM. METHODS: We performed a prospective study to compare liver fibrosis grade with fibrosis score. LSM was measured using magnetic resonance elastography in 184 patients that underwent liver resection, and liver fibrosis grade was diagnosed histologically after surgery. Using the prediction model established in the training group, we validated the classification accuracy in the independent test group. RESULTS: First, we determined a cut-off value for stratifying fibrosis grade using LSM in 122 patients in the training group, and correctly diagnosed fibrosis grades of 62 patients in the test group with a total accuracy of 69.3%. Next, on least absolute shrinkage and selection operator analysis in the training group, LSM (r = 0.687, P < 0.001), indocyanine green clearance rate at 15 min (ICGR15) (r = 0.527, P < 0.001), platelet count (r = -0.537, P < 0.001) were selected as variables for the liver fibrosis prediction model. This prediction model applied to the test group correctly diagnosed 32 of 36 (88.8%) Grade I (F0 and F1) patients, 13 of 18 (72.2%) Grade II (F2 and F3) patients, and 7 of 8 (87.5%) Grade III (F4) patients in the test group, with a total accuracy of 83.8%. CONCLUSIONS: The prediction model based on LSM, ICGR15, and platelet count can accurately and reproducibly predict liver fibrosis grade.

Network-based analysis for identification of candidate genes for colorectal cancer progression.

Although high-throughput biological technologies have been producing a vast amount of multi-omics data regarding cancer genomics and several disease susceptible genes have been reported, many of these genes are likely to be irrelevant for the cancer process because only one feature of the tumor pathway could be focused on. By identifying 'CpG core', which was extracted from CpG sites in genomic DNA by our newly developed method, we performed integrated analysis using gene expression and DNA methylation profiles of 116 colorectal cancer samples. First, based on gene expression values, colorectal cancer samples were divided into three clusters (Cluster-1, -2, and -3) by k-means clustering. The 5-year overall survival rates of colorectal cancer patients were 74.8%, 29.2%, and 29.4% in Cluster-1, -2, and -3, respectively, and the prognosis of Cluster-2 was significantly poorer than that of the other two clusters owing to liver metastasis (P < 0.001). Second, each cluster was divided into two subgroups based on methylation status, and the 5-year overall survival rate of Cluster-1H (36.8%) was significantly shorter than that of Cluster-1L (96.1%) due to the accumulation of aberrant DNA methylation (P = 0.014). Third, network-based analysis using expression and methylation profiles demonstrated that nucleoporin family genes were downregulated in Cluster-2 and that the PTX3 gene was highly methylated in Cluster-1H. These combined data indicate that integrated analysis can identify disease characteristics that would be missed using single comprehensive analysis, and that multiple pathways would play pivotal roles in the liver metastasis of colorectal cancer.

Early hepatocellular carcinoma as a signaling lesion for subsequent malignancy.

OBJECTIVE: Early diagnosis and treatment of cancer may contribute substantially to complete cure, but it remains unknown whether treatment of early hepatocellular carcinoma can actually result in cure. This study was performed to clarify the cancer risk of the background liver after treating early hepatocellular carcinoma. METHODS: Early hepatocellular carcinoma is defined as very well-differentiated cancer containing Glisson's triad. The cumulative incidence of classical hepatocellular carcinoma, hypervascular liver cancer detected on imaging studies, after resection of early hepatocellular carcinoma positive for anti-hepatitis C antibody (early hepatocellular carcinoma group, n = 105) was compared with that in patients with chronic liver disease positive for anti-hepatitis C antibody (control group, n = 751) and propensity score-matched patients after resection of classical hepatocellular carcinoma (classical hepatocellular carcinoma group, n = 105). RESULTS: After a median follow-up of 4.8 years (range, 0.3-15.0), the cumulative incidence of classical hepatocellular carcinoma at 5 years was 56.9% (95% confidence interval, 44.2-67.7%) in the early hepatocellular carcinoma group and 70.6% (52.5-81.8%) in the classical hepatocellular carcinoma group as compared with 4.6% (2.8-6.4%) in the control group. The risk of the development of classical hepatocellular carcinoma in the early hepatocellular carcinoma group was significantly higher than that in the control group (hazard ratio, 17.5; 95% confidence interval, 12.1-25.3; P < 0.001) and significantly lower than that in the classical hepatocellular carcinoma group (hazard ratio, 0.60; 0.41-0.89; P = 0.010). However, the cumulative incidence of second primary hepatocellular carcinoma in patients with one early hepatocellular carcinoma did not differ significantly from that in patients with two or more early hepatocellular carcinoma lesions (hazard ratio, 1.50; 0.85-2.65; P = 0.157). CONCLUSIONS: Treatment of early hepatocellular carcinoma cannot provide complete cure due to the substantial risk of developing classical hepatocellular carcinoma.

No Need of Immediate Treatment for Hypovascular Tumors Associated with Hepatocellular Carcinoma.

BACKGROUND: Hypovascular tumors associated with hepatocellular carcinoma (HCC) can be diagnosed, but it remains unknown whether such lesions should be treated immediately. This study aimed to clarify the clinical significance of treating hypovascular liver nodules. METHODS: After diagnosis of hypovascular tumors smaller than 3 cm, 104 patients underwent liver resection immediately (Group 1), while 93 patients were placed under observation (Group 2). In Group 1, 98 patients were diagnosed as having HCC (Group 1'), while 80 patients in Group 2 underwent liver resection after vascularization or appearance of other hypervascular HCC (Group 2'), eight patients had been observed, and five patients could not undergo operation due to appearance of other multiple HCCs. To avoid lead time bias for tumor vascularization, survival rates of patients after diagnosis of hypovascular tumors as well as those after operation in the two groups were compared. RESULTS: After a median follow-up of 3.3 years (range 0.6-11.2), the 5-year overall survival rates after liver resection of Group 1' (74.8 %; 95 % CI 64.3-86.1) was significantly higher than that of Group 2' (59.2 %; 46.4-75.6; P = 0.027). However, the 5-year overall survival rates after diagnosis of hypovascular liver nodules of Group 1' (74.7 %; 66.1-85.0) was not significantly different from that of Group 2' (77.1 %; 67.0-88.6; P = 0.761). Consequently, the 5-year overall survival rate after diagnosis of Group 2 (75.6 %; 64.7-83.1) was not significantly different from that of Group 1 (73.2 %; 67.5-86.1; P = 0.591) by intention-to-treat analysis. CONCLUSIONS: It is not necessary to treat hypovascular liver tumors immediately after diagnosis.

Clinical score to predict the risk of bile leakage after liver resection.

BACKGROUND: In liver resection, bile leakage remains the most common cause of operative morbidity. In order to predict the risk of this complication on the basis of various factors, we developed a clinical score system to predict the potential risk of bile leakage after liver resection. METHODS: We analyzed the postoperative course in 518 patients who underwent liver resection for malignancy to identify independent predictors of bile leakage, which was defined as "a drain fluid bilirubin concentration at least three times the serum bilirubin concentration on or after postoperative day 3," as proposed by the International Study Group of Liver Surgery. To confirm the robustness of the risk score system for bile leakage, we analyzed the independent series of 289 patients undergoing liver resection for malignancy. RESULTS: Among 81 (15.6 %) patients with bile leakage, 76 had grade A bile leakage, and five had grade C leakage and underwent reoperation. The median postoperative hospital stay was significantly longer in patients with bile leakage (median, 14 days; range, 8 to 34) than in those without bile leakage (11 days; 5 to 62; P = 0.001). There was no hepatic insufficiency or in-hospital death. The risk score model was based on the four independent predictors of postoperative bile leakage: non-anatomical resection (odds ratio, 3.16; 95 % confidence interval [CI], 1.72 to 6.07; P < 0.001), indocyanine green clearance rate (2.43; 1.32 to 7.76; P = 0.004), albumin level (2.29; 1.23 to 4.22; P = 0.01), and weight of resected specimen (1.97; 1.11 to 3.51; P = 0.02). When this risk score system was used to assign patients to low-, middle-, and high-risk groups, the frequency of bile leakage in the high-risk group was 2.64 (95 % CI, 1.12 to 6.41; P = 0.04) than that in the low-risk group. Among the independent series for validation, 4 (5.7 %), 16 (10.0 %), and 10 (16.6 %) patients in low-, middle, and high-risk groups were given a diagnosis of bile leakage after operation, respectively (P = 0.144). CONCLUSIONS: Our risk score model can be used to predict the risk of bile leakage after liver resection.

DNA methylation status as a biomarker of anti-epidermal growth factor receptor treatment for metastatic colorectal cancer.

Anti-epidermal growth factor receptor (EGFR) treatment is an effective option for metastatic colorectal cancer (CRC) treatment. However, there are few reliable biomarkers to predict the clinical response to anti-EGFR treatment. We investigated the genome-wide DNA methylation status in metastatic colorectal cancer to identify associations between the methylation status and clinical response to anti-EGFR antibody. We retrospectively reviewed the medical records of 97 patients (45 patients for the first cohort and 52 patients for the second cohort) who received anti-EGFR treatment for KRAS wild-type metastatic CRC. Then we analyzed the associations between genome-wide DNA methylation status and clinical response to anti-EGFR treatment, and evaluated the predictive power and value of the methylation status statistically. As a result, each cohort was classified into highly methylated CRC and low methylated CRC subgroups by unsupervised clustering analyses. In the first cohort, clinical outcomes were significantly better in the low methylated CRC subgroup than in the highly methylated CRC subgroup (response rate, 35.7% vs 6.3%, P = 0.03; disease control rate, 75% vs 31.3%, P = 0.005; hazard ratio for progression-free survival, 0.27; 95% confidence interval, 0.13-0.57, P < 0.001; overall survival, 0.19; 95% confidence interval, 0.06-0.54, P < 0.001). These results were reproducible in the second cohort. The genome-wide methylation status was a predictive factor of progression-free survival and overall survival independently of RAS mutation status. In conclusion, we found that the genome-wide DNA methylation status is a powerful epigenetic predictor of anti-EGFR treatment in patients with KRAS wild-type metastatic colorectal cancer (UMIN000005490).

Surgical outcomes in patients with hepatocellular carcinoma associated with metabolic syndrome.

BACKGROUND: Only a few papers have focused on the surgical outcomes of patients with hepatocellular carcinoma (HCC) associated with the metabolic syndrome. We compared the outcomes of patients with metabolic HCC with those of patients with non-B, non-C HCC associated with other etiologies. METHODS: Metabolic HCC was defined as HCC arising in patients with at least three of the following metabolic disorders: central obesity, dyslipidemia, hypertension, and diabetes mellitus. A total of 246 patients with non-B, non-C HCC were divided into three groups: metabolic HCC (n = 35), alcoholic HCC (n = 114), and cryptogenic HCC (n = 97). Clinical characteristics, surgical data, and survival were compared among the three groups. RESULTS: Metabolic HCC was diagnosed at a significantly higher age than alcoholic (75 vs. 68 years, P = 0.004) and cryptogenic HCCs (75 vs. 71 years, P = 0.027). Postoperative complications occurred significantly higher in patients with metabolic HCC compared with those with cryptogenic HCC (40.0 vs. 22.7 %, P = 0.049). Especially, pulmonary complications were significant in metabolic HCC compared with cryptogenic HCC (22.9 vs. 8.2 %, P = 0.023). The overall survival rates in the metabolic, alcoholic, and cryptogenic HCC groups were 96.7 % (95 % CI, 90.5-100), 96.3 % (95 % CI, 92.8-99.9), and 95.6 % (95 % CI, 91.5-99.9) at 1 year, respectively, and 87.2 % (95 % CI, 74.5-100), 82.9 % (95 % CI, 74.6-92.2), and 84.5 % (95 % CI, 75.7-94.3) at 3 years, respectively (P = 0.84). The disease-free survival rates in each group were 74.4 % (95 % CI, 60.5-91.5), 76.9 % (95 % CI, 69.2-85.5), and 74.3 % (95 % CI, 65.0-84.8) at 1 year, respectively, and 29.3 % (95 % CI, 16.6-51.8), 39.0 % (95 % CI, 29.7-51.2), and 41.1 % (95 % CI, 29.7-56.8) at 3 years, respectively, (P = 0.90). CONCLUSIONS: Metabolic HCC patients have specific risks of postoperative complication related to the metabolic syndrome.