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Tumor seeding in the chest wall was depicted at follow-up CT obtained 9 months after radiofrequency ablation for hepatocellular carcinoma. Transcatheter arterial embolization was successfully performed, injecting emulsion of 10 mg of epirubicin and 1 ml of iodized oil followed by gelatin sponge particles via the microcatheter placed in the right eleventh intercostal artery. The patient died of tumor growth in the liver one year after the embolization, but no progression of the tumor seeding was noted during the follow-up period. We conclude that transcatheter arterial embolization was effective for the control of tumor seeding after radiofrequency ablation for hepatocellular carcinoma.

Recurrent chromosomal gains at 1q, 6p, 8q, and 17q, or losses at 1p, 4q, 6q, 8p, 9p, 13q, 16q, and 17p are common features of human hepatocellular carcinoma (HCC). For precise determination of the shortest region of overlap (SRO), 49 HCC obtained at the time of surgery or autopsy were subjected to comprehensive microsatellite analysis by using 400 markers distributed at almost equal distances throughout the 22 autosomes and X chromosomes. Each allele showing imbalance was subjected to comparative duplex polymerase chain reaction using a retained allele as an internal control to determine whether the imbalance was the result of chromosomal gain or loss. The following SRO of recurrent chromosomal gains and losses were determined: -1p36.22 approximately p36.33, D1S450-D1S2893, 5.0 mega-base pairs (Mbp); +1q23.3 approximately q25.3, D1S2878-D1S2619, 16.9 Mbp; -4q21.2 approximately q24, D4S2964-D4S1572, 23.0 Mbp; -6q23.3 approximately qter, D6S292-qter, 34.7 Mb; -8p22 approximately p23.1, D8S549-D8S550, 4.8 Mbp; +8q12.2 approximately q24.13, D8S260-D8S514, 61.8 Mbp; -13q13.3 approximately q22.1, D13S218-D13S156, 35.6 Mbp; -16q22.1 approximately qter, D16S503-qter, 26.7 Mbp; and -17p12 approximately pter, D17S921-pter, 14.2 Mbp. Contrary to our initial expectations, many HCC showed major deletions or additions of chromosome arms, so that a number of genes were included in the SRO. Although some putative oncogenes or tumor suppressor genes mapped in these SRO may be important, relative copy number changes of numerous other genes may affect pathogenesis of HCC.

It is widely accepted that chromosomal instability is an essential feature of cancer cells including hepatocellular carcinoma (HCC) cells. For an accurate characterization of clonal evolution of HCC cells, we studied chromosomal alterations in various metastatic lesions in an autopsy case of HCC. Tissues from the main tumor, which consisted of 2 macroscopically distinct portions, and from intrahepatic metastasis, portal vein thrombus, epiploic lymph node metastasis, and pulmonary metastasis as well as from the non-tumorous liver were analyzed with comprehensive microsatellite analysis. Alleles showing imbalance of the main tumor were further subjected to comparative duplex PCR, with use of a retained allele as an internal control, to determine whether the imbalance was the result of chromosomal gain or loss. A striking finding was that allelic imbalances detected in the main tumor and metastatic lesions were almost identical, showing -1p, +1q, -4q, -7, -8p, +8q, +9q, +10, -13q, -17p, +19p, -19q, and -X. Additional alterations of +2q and -16q were detected in one portion of the main tumor and the portal vein thrombus. In conclusion, clonal evolution of the HCC cells during metastatic progression seems rare, in contrast to many recurrent chromosomal aberrations that may have accumulated before the clinical manifestation.

Recurrent chromosomal gain at 1q is one of the most common features of human hepatocellular carcinoma (HCC), but how the gain at 1q contributes to hepatocarcinogenesis is still unclear. To identify the target genes, precise determination of the shortest region of overlap (SRO) and of breakpoints is necessary. Similarly, the role of loss at 1p, which is also a major cytogenetic aberration in HCC, needs to be determined. Fifty HCCs were examined with the aid of 59 microsatellite markers distributed throughout both arms of chromosome 1. To detect allelic gain effectively, the cutoff value of the allelic imbalance index was set at 0.70. Alleles showing imbalance were subjected to multiplex PCR, using a retained allele as an internal control, to determine whether the imbalance was the result of chromosomal gain or loss. The SRO of the gains was defined as D1S2878-D1S2619 (1q23.-q25.3, 16.9 Mb), which involved 36 cases (72%). Gains in the number of copies of certain oncogenes within this region seemed to be critical for the pathogenesis of HCC. In contrast, the centromeric breakpoints of these gains varied, but they tended to occur mainly in the pericentromeric region (26 of 50 cases, 52%). Rearrangement of specific genes associated with the gains is unlikely. On the other hand, the SRO of deletion was defined as D1S2893-D1S450 (1p36.32-p36.22, 5.1 Mb). Four known putative tumor-suppressor genes (TP73, RIZ1, NBL1/DAN, and CDKN2C) were outside the SRO, suggesting the presence of other candidate genes with critical roles in hepatocarcinogenesis.

Allelic imbalance (AI), which represents certain chromosomal gains or losses, has been described in human hepatocellular carcinoma (HCC), but the impact of AI on the early stage of hepatocarcinogenesis has not been fully clarified. Moreover, no previous allelotype studies have identified the difference in chromosomal gain and loss that results in AI. To resolve these problems, we examined 18 well-differentiated HCCs with comprehensive allelotyping by using 400 microsatellite markers with semiquantitative assessment of chromosomal gain or loss. To detect allelic gain effectively, the cutoff value of the allelic imbalance index was set at 0.70. Each allele showing imbalance was subjected to multiplex PCR with use of a retained allele as an internal control to determine whether the imbalance was the result of chromosomal gain or loss. High frequencies of chromosomal gains were detected at 1q (D1S196-D1S2785, 56%), 5q (D5S647-D5S2027, 44%), 6p (6pter-D6S309, 33%), 7 (7pter-D7S657, 22%), and 8q (D8S514-qter, 44%), whereas chromosomal losses were frequently observed at 1p (1pter-D1S234, 22%), 8p (8pter-D8S549, 44%), and 17p (17pter-D17S921, 28%). The extent of overall chromosomal aberration was closely related to the maximum tumor diameter (P = 0.002) and the presence of hepatitis B surface antigen (P = 0.03). Recurrent chromosomal losses at 1p and 8p and gains at 1q and 8q, even in HCCs with a minimal extent of aberrant chromosomes, indicate that these alterations were critical in the early stage of hepatocarcinogenesis. On the other hand, deletions of 13q and 16q were infrequent and were seen only in the most aberrant cases, which suggested that these were late events.

Objectives: Early detection of precancerous lesions and early-stage cancers are essential to reduce mortality from colorectal cancer (CRC). Serum/plasma microRNAs (miRs) have been reported as diagnostic and prognostic biomarkers of CRC, but their utility in detecting patients with early lesions has not been fully explored. The aim of this study is to identify serum miRs which are potentially useful as diagnostic biomarkers for early colorectal neoplasms, and potential confounders in a blood test. Methods: Candidate biomarker miRs were selected from previously published studies. Serum samples were collected from patients with low-grade intraepithelial neoplasias (LGINs) including tubular adenomas and tubulovillous adenomas, high-grade intraepithelial neoplasias (HGINs), early cancers, and healthy volunteers, and divided into discovery and validation sets. Total RNA was extracted from serum samples and levels of candidate miRs were measured by real-time RT-PCR. To evaluate the impact of hemolysis on serum miR levels, serially diluted hemolysed controls were prepared from stock solution made by hemolysing the red blood cells in distilled water. Levels of candidate miRs in hemolysed controls were also examined by real-time RT-PCR. Absorbance of serum samples at 560 nm, 576 nm, and 592 nm was measured by spectrophotometry and hemoglobin levels were estimated from a standard curve. Results: Fourteen miRs were selected as candidate diagnostic biomarkers of early colorectal neoplasms from a review of the literature. Serum levels of five miRs were too low to be accurately quantified by real-time RT-PCR, and excluded from further evaluation. Sera from 12 patients with LGINs, 8 patients with HGINs, 4 patients with cancers, and 25 healthy volunteers were included in the discovery phase. Of 9 miRs examined, miR21 (p = 0.0007), miR29a (p < 0.0001) and miR125b (p = 0.0198) showed significantly higher levels in sera from early colorectal neoplasms compared to those from healthy volunteers. Higher levels of miR29a and miR125b in sera from early colorectal neoplasms were confirmed in the validation phase using independent set of samples. Levels of miR21, 29a, and miR125b in sera significantly correlated with the degree of hemolysis. Conclusions: Serum miRs may be useful biomarkers to detect patients with early colorectal neoplasia, including adenomas. Hemolysis affects serum miR levels, and will confound measurement. Since hemolysis occurs frequently during blood collection, its impact on serum miRs should be further investigated. Citation Format: Atsushi Yamada, Takahiro Horimatsu, Yoshinaga Okugawa, Naoshi Nishida, Tadayuki Kou, Toshihiro Kusaka, Hajime Honjo, Yusuke Amanuma, Osamu Kikuchi, Manabu Muto, Ajay Goel, C. Richard Boland. Serum microRNAs as diagnostic biomarkers for early colorectal neoplasms. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 867. doi:10.1158/1538-7445.AM2014-867

Aim: The present study aimed to discover novel epigenetic biomarkers that could permit identification of CRC patients who are at high-risk of developing tumor recurrence following curative surgery and who are at high-risk of imminent tumor progression following treatments for unresectable cancer. Methods: Given that previous studies have clearly shown that microsatellite stable (MSS) CRC with BRAF mutations have worse outcomes compared to other subgroups, in the initial discovery phase we analyzed a 17-gene methylation biomarker panel consisting of differentially methylated loci in BRAF mutant (V600E) CRCs with microsatellite instability (MSI) and MSS. In the validation phase, we analyzed an independent cohort of 255 stage II/III CRCs that underwent curative resection and 103 stage IV CRCs. Results: We identified that among the 17-genes methylation panel; only MGMT methylation levels were predictive of disease recurrence in CRC. Extensive methylation of the MGMT promoter region was observed in 22% of stage II/III and 16% of stage IV CRCs, and this was significantly associated with relapse -free survival (RFS) (p = 0.03 by Wilcoxon test), but not with overall survival (p = 0.96 by Wilcoxon test) in stage II/III CRC following curative resection. By using Cox proportional hazards regression, for all stage II and III cases, the relative risk ratio for RFS was 2.2 (95%CI; 1.1 to 5.6, p = 0.0359) in MGMT unmethylated vs. methylated CRCs and was 0.62 (0.034 to 3.2, p = 0.627) in MSI vs. MSS CRCs. Of 103 stage IV CRCs, 69(68%) patients were diagnosed as unresectable (unresectable group) cases and 32 (32%) were resectable (resectable group). MGMT methylation was significantly improved overall survival in unresectable group (HR = 0.43 (0.17 to 0.94), p = 0.03, Cox proportional hazards regression). Conclusions: Our data firstly highlight the importance of MGMT methylation status as one of the promising predictive biomarkers that can robustly identify patients who are at risk for disease recurrence in patients following curative surgery in stage III CRC patients and predict the outcomes of stage IV CRC patients with unresectable disease lesions at the time of diagnosis. Disclosure: All authors have declared no conflicts of interest.

Radiofrequency ablation (RFA) is commonly applied for the treatment of hepatocellular carcinoma (HCC) because of the facile procedure, and the safety and effectiveness for the treatment of this type of tumor. On the other hand, it is believed that HCC cells should spread predominantly through the blood flow of the portal vein, which could lead to the formation of intrahepatic micrometastases. Therefore, monitoring tumor response after the treatment is quite important and accurate assessment of treatment response is critical to obtain the most favorable outcome after the RFA. Indeed, several reports suggested that even small HCCs of ≤ 3 cm in diameter might carry intrahepatic micrometastases and/or microvascular invasion. From this point of view, for preventing local recurrences, RFA should be performed ablating a main tumor as well as its surrounding non-tumorous liver tissue where micrometastases and microvascular invasion might exist. Recent advancement of imaging modalities such as contrast-enhanced ultrasonic, computed tomography, and magnetic resonance imaging are playing an important role on assessing the therapeutic effects of RFA. The local recurrence rate tends to be low in HCC patients who were proven to have adequate ablation margin after RFA; namely, not only disappearance of vascular enhancement of main tumor, but also an adequate ablation margin. Therefore, contrast enhancement gives important findings for the diagnosis of recurrent HCCs on each imaging. However, hyperemia of non-tumorous liver surrounding the ablated lesion, which could be attributed to an inflammation after RFA, may well obscure the findings of local recurrence of HCCs after RFA. Therefore, we need to carefully address to these imaging findings given the fact that diagnostic difficulties of local recurrence of HCC. Here, we give an overview of the current status of the imaging assessment of HCC response to RFA.

Background: Downregulated expression of the netrin-1 dependence receptors, UNC5C and DCC, is a frequent event in significant proportion of colorectal tumors. However, the tumor suppressive role of this important cancer-related pathway in other gastrointestinal cancers remains unclear. We hypothesized that similar to colorectal cancer, down-regulation of UNC5C and DCC may have an important growth-regulatory function in gastric tumorigenesis as well. Methods: We performed a series of genetic (loss of heterozygosity, LOH) and epigenetic analysis (aberrant DNA methylation) for UNC5C and DCC in a cohort of 105 sporadic gastric cancers and the corresponding normal gastric mucosa. Results: In this study, the distribution of gastric cancers as categorized by TNM staging system (UICC 7th) was as follows; 20, 24, 28, and 29 cases in stages I, II, III, and IV, respectively. Overall, 58% (48 out of 83 informative cases) and 76% (65 out of 85 informative cases) of gastric cancers demonstrated either a genetic or epigenetic alteration in the UNC5C and DCC genes, respectively. Interestingly, although epigenetic mechanisms were the primary cause for UNC5C inactivation, methylation-induced transcriptional silencing served also served as the second hit responsible for the DCC gene loss. Taken together, 52% (36 out of 69 gastric cancers with informative data) of gastric cancers showed cumulative defects in these two dependence receptors. The frequency of LOH and aberrant methylation of both dependence receptors gradually increased with progressive tumor stages. Conclusions: This is the first study that unravels the observation that majority of gastric cancers harbor defects in netrin1 receptors. Our observation that both genetic and epigenetic alterations are present early, and continue to escalate in a stepwise manner with the disease progression, highlights the fundamental importance of this growth regulatory pathway in gastric carcinogenesis.

Background and aim: Intestinal-type gastric carcinomas progress through chronic inflammation and atrophic gastritis. Heat shock protein 27(HSP27), a stress-induced molecular chaperone, inhibit reactive oxygen species (ROS) accumulation. In previous reports have been suggested that HSP27 plays an important role in inflammation and carcinogenesis. We investigated HSP27 expression in gastric neoplasia and background gastric mucosa to assess its involvement in gastric carcinogenesis. Methods:We used real-time quantitative polymerase chain reaction to examine HSP27 expression in gastric neoplasias and in gastric mucosae of 30 patients with intraepithelial neoplasias and in gastric mucosae of 30 patients without gastric neoplasia. Immunohistochemical staining was performed on 30 advanced gastric cancer tissues. Results: HSP27 expression was negatively associated with atrophic gastritis. HSP27 expression in the background gastric mucosa of those without gastric neoplasia(P= 0.004).In tumor necrosis factor -treated gastric cancer cell,HSP27 knockdown increased cell death and ROS accumulation that link inflammation to cancer. Poorly differentiated tumors most frequently had high HSP27 levels. Dedifferentiated of cancer cells is associated with an epithelial-mesenchymal transition signaling pathway. In gastric cancer MKN-1 cells, HSP27 knockdown upregulated E-cadherin and downregulated vimentin and smooth muscle actin, but this did not occur in MKN-74 cells. Conclusion: HSP27 expression in gastric mucosae is negatively correlated with intraepithelial neoplasia, a probable precursor to gastric cancer and HSP27 expression in cancer is positively correlated with poor differentiation.

Introduction: Epidemiological studies have shown that nonalcoholic fatty liver disease (NAFLD) not only is a possible precursor of cirrhosis, but also has been associated with metabolic syndrome, diabetes and cardiovascular disease. There is a need to find a biomarker which proves to be reliable, non-invasive, and easy to perform in clinical practice. Our aim was to know whether serum alanine aminotransferase (ALT) value is a reliable biomarker of liver fat content in subjects with NAFLD in the general population, and to determine if the current threshold of normality for ALT is appropriate to assess the presence of liver fat in these subjects. Methods: This is a cross-sectional, randomized, prospective, populationbased study. We studied 120 healthy subjects attending health screening centers, alcohol consumption less than 50 g/week. Subjects underwent blood tests including aminotransferases. Viral hepatitis, autoimmune, drugs and others causes of liver disease were excluded. Measurements: quantification of liver fat content by spectroscopy 1H MR with magnetic field strength of 3 tesla. We used a cut off value .5% of liver fat content as the upper limit of normal for the diagnosis of hepatic steatosis (1). Serum ALT levels by commercially available kits. Results: There was an excellent positive correlation between liver fat content and serum levels of ALT (r = 0.73, p ,0.0001). All subjects with ALT values .37 U/L had hepatic steatosis (PPV: 100%) and none of the subjects with ALT ,20 U/L had steatosis (NPV: 100%). ROC curves were created, obtaining that the cutoff value that represents the normal threshold for the diagnosis of NAFLD was ALT: 23 U / L (sensitivity: 94.67%, specificity 73.91%, PPV: 85.84%, NPV: 89.47%). Conclusion: This study shows that serum ALT levels could be a reliable biomarker of NAFLD if the upper limit of normal for ALT is set at 23 U/L.

Global DNA hypomethylation and regional hypermethylation in CpG island has been recognized as common feature of cancer DNA, including that of hepatocellular carcinoma (HCC). However, precise mechanism underlying the alteration of methylation is still unclear. We conducted a genome-wide methylation analysis to elucidate distribution and characteristics of genes that subject to cancer-related DNA methylation in human HCC. With written informed consent, 20 HCC and 3 corresponding matched non-cancerous liver tissues were obtained at the time of hepatectomy (2 tumors) or orthotopic living-donor liver transplantation (17 tumors and 3 non-tumors). After bisulfite modification, the converted DNA was subject to hybridization on Infinium Human Methylation BeadChip 450K (Illumina, Inc., San Diego, CA) that contained 485,577 CpGs of the human genome including gene promoters and repetitive DNA elements. The methylation level for each CpG was represented as a beta value according to the fluorescent intensity ratio. In order to identify alteration of methylation profile between HCC and non-tumor liver, difference of average beta values between tumor and non-tumor was calculated. Of 485,577 CpG loci, differences of average beta values of 460,036 loci (94.7%) were within 30%. These were considered as constitutively methylated or unmethylated. Tumor-specific hypomethylation was found at 18,807 loci. Of these, 65.1% were located outside CpG islands, shore or shelf (so-called ‘open sea’). Tumor-specific demethylation rarely occurred within CpG islands (6.5%). On the other hand, tumor-specific DNA methylation was found at 6734 loci. Of these, 77.6% were located within CpG islands. Interestingly, normally methylated CpGs (average beta value < 0.20) were mainly located in CpG islands (95,943 of 138,081, 69.0%), and many of normally unmethylated or variably methylated CpGs were located in the open sea (165,209 of 347,496, 47.5%). Tumor-specific methylation occurring at CpG islands, may simply be dependent on the distribution of normally unmethylated CpGs. This finding may help us target epigenetically silenced tumor suppressor genes. Citation Format: Takafumi Nishimura, Yukiko Mori, Naoshi Nishida. Landscape of DNA methylation status of human hepatocellular carcinoma revealed by Human Methylation BeadChip 450K. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4249. doi:10.1158/1538-7445.AM2013-4249

Background. This study was performed to develop a sensitive method for the detection of circulating hepatocellular carcinoma (HCC) cells in peripheral blood, in advance of the diagnosis of distant metastasis of HCC by conventional means. Methods. Peripheral blood (5 ml) samples were obtained from 64 patients with HCC and from 48 control subjects (31 patients with benign liver disease, 8 with metastatic liver cancer, and 9 with normal liver function). To identify HCC cells in peripheral blood, liver-specific human alpha-fetoprotein (hAFP) mRNA was amplified from total RNA extracted from whole blood by reverse transcriptase-polymerase chain reaction. Results. Human alpha-fetoprotein mRNA was detected in 23 blood samples from the HCC patients (23/64, 36%), in 17 patients in whom there was no clinical evidence of distant metastasis. In contrast, there were no control patients whose samples showed detectable hAFP mRNA in the peripheral blood. The presence of hAFP mRNA in blood seemed to be correlated with the stage (by TNM classification) of HCC, the serum hAFP value, and the presence of intrahepatic metastasis, portal vein thrombosis, and/or distant metastasis. Conclusions. Reverse-transcriptase polymerase chain reaction is a very sensitive method for detecting circulating HCC cells. With this technique, important information for the management of HCC can be acquired, such as the indications for orthotopic liver transplantation in HCC patients. Moreover, use of this detection method may encourage investigation of the mechanism of metastasis in HCC. Cancer 1995 ;75 :2214-9.

Aim. We assessed the usefulness of post-vascular images on contrast-enhanced ultrasonography (CE-US) in the gross classification of hepatcellular carcinoma (HCC) in comparison with contrast-enhanced CT (CE-CT) findings. Methods. 51 patients with 61 HCCs underwent hepatectomy, and the gross type of HCCwas estimated by CE-US and CE-CT.We assessed the tumor shape by defect images during the post-vascular phase onCE-US using perfluorocarbon microbubbles, whereas the positive enhancement in the arterial phase and wash-out in the equilibrium phase on CE-CT. Patients were divided into two subgroups according to the gross classification: simple nodular type and non-simple nodular type. The capability of each imaging modality to correctly depict tumor shapes was compared. Results. Thirty-nine tumors were macroscopically diagnosed as simple nodule type, 19 tumors as simple nodular type with extranodular growth, and 3 tumors as confluent multinodular type from the resected specimen. The sensitivity and specificity of CE-US to diagnose the non-simple nodule type HCC were 86.4% and 89.7%, while those of CE-CT were 68.2% and 76.9%, respectively. The accuracy was significantly better in CE-US compared with CE-CT (88.5% vs 73.8%; p=0.037). Conclusion. The post-vascular phase image of CE-US is a more reliable tool to evaluate the gross type of HCC than CE-CT and is considered to be essential for the determination of treatment strategy and to estimate the prognosis of HCC patients. The sensitivity, specificity and accuracy of the gross type of HCC on CE-CT and CE-US

Tenofovir-Emtricitabine) have undetectable viral load at the present time. Conclusion: 1) Cirrhosis, advanced HCC and co-infection with HIV are not uncommon in patients with chronic HBV who have emigrated from Africa. 2) The majority of these patients are eligible for treatment of HBV infection. 3) Early identification, treatment, and screening for liver cancer in patients who have emigrated from Africa is warranted based on our findings

Colorectal cancers (CRCs) with the CpG island methylator phenotype (CIMP) often associate with epigenetic silencing of hMLH1 and an activating mutation in the BRAF gene. However, the current CIMP criteria are ambiguous and often result in an underestimation of CIMP frequencies in CRCs. Because BRAF and KRAS belong to same signaling pathway, we hypothesized that not only mutations in BRAF but mutant KRAS may also associate with CIMP in CRC.We determined the methylation status in a panel of 14 markers (7 canonical CIMP-related loci and 7 new loci), microsatellite instability status, and BRAF/KRAS mutations in a collection of 487 colorectal tissues that included both sporadic and Lynch syndrome patients.Methylation analysis of 7 CIMP-related markers revealed that the mean number of methylated loci was highest in BRAF-mutated CRCs (3.6) vs KRAS-mutated (1.2, P.0001) or BRAF/KRAS wild-type tumors (0.7, P.0001). However, analyses with 7 additional markers showed that the mean number of methylated loci in BRAF mutant tumors (4.4) was the same as in KRAS mutant CRCs (4.3, P = .8610). Although sporadic microsatellite instability high tumors had the highest average number of methylated markers (8.4), surprisingly, Lynch syndrome CRCs also demonstrated frequent methylation (5.1).CIMP in CRC may result from activating mutations in either BRAF or KRAS, and the inclusion of additional methylation markers that correlate with mutant KRAS may help clarify CIMP in future studies. Additionally, aberrant DNA methylation is a common event not only in sporadic CRC but also in Lynch syndrome CRCs.

9551 Background: It is widely accepted that chromosomal instability is one of the essential features of cancer cells and that significant intratumoral heterogeneity based on the genetic changes may...

Background We conducted a multicenter randomized clinical trial to determine the optimal treatment strategy against chronic hepatitis C virus (HCV) with genotype 1b and a high viral load (G1b/high). Methods The study subjects included 153 patients with G1b/high. Patients were initially treated with PEG-IFNα-2a alone and then randomly assigned to receive different treatment regimens. Ribavirin (RBV) was administered to all patients with HCV RNA at week 4. Patients negative for HCV RNA at week 4 were randomly assigned to receive PEG-IFNα-2a (group A) or PEG-IFNα-2a/RBV (group B). Patients who showed HCV RNA at week 4 but were negative at week 12 were randomly assigned to receive weekly PEG-IFNα-2a (group C) or biweekly therapy (group D). Patients who showed HCV RNA at week 12 but were negative at week 24 were randomly assigned to receive PEG-IFNα-2a/RBV (group E) or PEG-IFNα-2a/RBV/fluvastatin (group F). Results Overall, the rate of sustained virological response (SVR) was 46 % (70/153). The total SVR rate in the group (A, D, and F) of response-guided therapy was significantly higher than that in the group (B, C, and E) of conventional therapy [70 % (38/54) versus 52 % (32/61), p = 0.049]. Although IL28-B polymorphism and Core 70 mutation were significantly associated with efficacy, patients with rapid virological response (RVR) and complete early virological response (cEVR) achieved high SVR rates regardless of their status of IL-28B polymorphism and Core 70 mutation. Conclusion In addition to knowing the IL-28B polymorphism and Core 70 mutation status, understanding the likelihood of virological response during treatment is critical in determining the appropriate treatment strategy.

Background To test the hypothesis that use of the response evaluation criteria in cancer of the liver (RECICL), an improved evaluation system designed to address the limitations of the response evaluation criteria in solid tumors 1.1 (RECIST1.1) and modified RECIST (mRECIST), provides for more accurate evaluation of response of patients with hepatocellular carcinoma (HCC) to treatment with sorafenib, a molecularly targeted agent, as assessed by overall survival (OS). Methods The therapeutic response of 156 patients with advanced HCC who had been treated with sorafenib therapy for more than 1 month was evaluated using the RECIST1.1, mRECIST, and RECICL. After categorization as showing progressive disease (PD), stable disease (SD), or objective response, the association between OS and categorization was examined using the Kaplan–Meier method to develop survival curves. The 141 cases categorized as PD or SD by the RECIST1.1, but objective response by the mRECIST and RECICL, were further analyzed for determination of the association between OS and categorization. Results Only categorization using the RECICL was found to be significantly correlated with OS (p = 0.0033). Among the patients categorized as SD or PD by the RECIST1.1, reclassification by the RECICL but not the mRECIST was found to be significantly associated with OS and allowed for precise prediction of prognosis (p = 0.0066). Conclusions Only the use of the RECICL allowed for identification of a subgroup of HCC patients treated with sorafenib with improved prognosis. The RECICL should, therefore, be considered a superior system for assessment of therapeutic response. Electronic supplementary material The online version of this article (doi:10.1007/s00535-014-0936-0) contains supplementary material, which is available to authorized users.

Supplemental material, sj-docx-2-tam-10.1177_17588359211010937 for Antacid exposure and immunotherapy outcomes among patients with advanced hepatocellular carcinoma by Tomi Jun, Umut Ozbek, Sirish Dharmapuri, Camille Hardy-Abeloos, Huili Zhu, Jung-Yi Lin, Nicola Personeni, Tiziana Pressiani, Naoshi Nishida, Pei-Chang Lee, Chieh-Ju Lee, Hannah Hildebrand, Neil Nimkar, Sonal Paul, Petros Fessas, Muntaha Naeem, Dominik Bettinger, Uqba Khan, Anwaar Saeed, Yi-Hsiang Huang, Masatoshi Kudo, Lorenza Rimassa, Thomas U. Marron, David J. Pinato and Celina Ang in Therapeutic Advances in Medical Oncology

Supplemental material, sj-docx-3-tam-10.1177_17588359211010937 for Antacid exposure and immunotherapy outcomes among patients with advanced hepatocellular carcinoma by Tomi Jun, Umut Ozbek, Sirish Dharmapuri, Camille Hardy-Abeloos, Huili Zhu, Jung-Yi Lin, Nicola Personeni, Tiziana Pressiani, Naoshi Nishida, Pei-Chang Lee, Chieh-Ju Lee, Hannah Hildebrand, Neil Nimkar, Sonal Paul, Petros Fessas, Muntaha Naeem, Dominik Bettinger, Uqba Khan, Anwaar Saeed, Yi-Hsiang Huang, Masatoshi Kudo, Lorenza Rimassa, Thomas U. Marron, David J. Pinato and Celina Ang in Therapeutic Advances in Medical Oncology

Supplemental material, sj-docx-1-tam-10.1177_17588359211010937 for Antacid exposure and immunotherapy outcomes among patients with advanced hepatocellular carcinoma by Tomi Jun, Umut Ozbek, Sirish Dharmapuri, Camille Hardy-Abeloos, Huili Zhu, Jung-Yi Lin, Nicola Personeni, Tiziana Pressiani, Naoshi Nishida, Pei-Chang Lee, Chieh-Ju Lee, Hannah Hildebrand, Neil Nimkar, Sonal Paul, Petros Fessas, Muntaha Naeem, Dominik Bettinger, Uqba Khan, Anwaar Saeed, Yi-Hsiang Huang, Masatoshi Kudo, Lorenza Rimassa, Thomas U. Marron, David J. Pinato and Celina Ang in Therapeutic Advances in Medical Oncology

Supplemental material, sj-docx-1-tam-10.1177_17588359211010937 for Antacid exposure and immunotherapy outcomes among patients with advanced hepatocellular carcinoma by Tomi Jun, Umut Ozbek, Sirish Dharmapuri, Camille Hardy-Abeloos, Huili Zhu, Jung-Yi Lin, Nicola Personeni, Tiziana Pressiani, Naoshi Nishida, Pei-Chang Lee, Chieh-Ju Lee, Hannah Hildebrand, Neil Nimkar, Sonal Paul, Petros Fessas, Muntaha Naeem, Dominik Bettinger, Uqba Khan, Anwaar Saeed, Yi-Hsiang Huang, Masatoshi Kudo, Lorenza Rimassa, Thomas U. Marron, David J. Pinato and Celina Ang in Therapeutic Advances in Medical Oncology