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512 Background: Lenvatinib has been widely used as a leading oral multikinase inhibitor for advanced hepatocellular carcinoma (HCC) patients in real-world practice worldwide. However, in the global phase 3 study comparing the effectiveness of lenvatinib and sorafenib, only a limited population of patients were enrolled, excluding those who had a high-burden intrahepatic lesion or Child-Pugh class (C-P) B, who were likely to receive systemic therapy in the clinical practice. Currently, combination immunotherapy has replaced multikinase inhibitors as the standard first-line treatment. Therefore, this prospective study explored the safety and efficacy of lenvatinib in the patient population, which would be used in real-world practice. Methods: This was an open-label, multicenter, prospective study that enrolled patients who had advanced HCC with C-P A or B, treated with lenvatinib as first-line or second-line after atezolizumab plus bevacizumab (Atz + Bv) at 10 sites in Japan. The study included patients who had high tumor burden, defined as identifying either tumor volume of more than 50% of the liver, portal vein tumor thrombosis reaching the main trunk or the contralateral branch, or bile duct invasion at baseline (jRCTs031190017). Results: Between December 1, 2019, and September 30, 2021, 59 patients were recruited for this study. At the time of enrollment, 47 and 12 patients were classified as C-P A and B, respectively. This study included 11 patients with high tumor burden and 12 treated with second-line after Atz + Bv. All patients with high tumor burden and second-line treatment were classified as C-P A. Median overall survival of C-P A and B patients was 20.3 and 4.2 months, respectively. Similarly, progression-free survival according to modified RECIST (mRECIST) of C-P A and B patients was 4.8 and 2.8 months, respectively. Objective response rate (ORR) according to mRECIST in C-P A patients was 61.9%, whereas in C-P B patients was 25.0%. ORRs of high-burden group and second-line group were 80.0% and 40.0%, respectively. Major severe adverse events (AE) (≥grade 3) in C-P A patients were hypertension (41.3%) and proteinuria (23.9%). In contrast, those in C-P B patients were hyponatremia (41.7%), elevated aspartate aminotransferase (41.7%), hypertension (33.3%), decreased appetite (16.7%), diarrhea (16.7%), and proteinuria (16.7%). Discontinuation rate due to AE of C-P A and B patients was 17.4% and 33.3%, respectively. In high-burden and second-line groups, 10% and 20% discontinued lenvatinib due to AE, respectively. Conclusions: Lenvatinib is expected to be safe and effective in patients with advanced HCC who have a high tumor burden and second-line treatment after Atz + Bv, whereas liver function was maintained with C-P A. However, in C-P B, this study found lower efficacy and higher discontinuation rates due to AE compared with C-P A. Clinical trial information: s031190017 .

Background Conversion from sorafenib to regorafenib is primarily an evidence-based treatment strategy in patients with advanced hepatocellular carcinoma (HCC). This study aimed to assess the safety and efficacy of sequential therapy with sorafenib and regorafenib in patients with advanced HCC by analysis of outcomes in clinical practice with the aim to complement phase III findings. Methods The medical records of patients with advanced HCC receiving regorafenib were retrieved to collect data on sorafenib administration at seven Japanese institutions. Radiological responses and adverse events were evaluated using the Response Evaluation Criteria in Solid Tumors version 1.1 and the Common Terminology Criteria for Adverse Events version 4.0, respectively. Results Before March 2018, 44 patients were administered regorafenib for advanced HCC. The median sorafenib treatment duration was 8.4 months. The most common adverse events were similar to those reported by the RESORCE trial. The median overall survival (OS) was 17.3 months (95% confidence interval [CI] 11.4–22.9), and 17 of 37 patients (45.9%) discontinued regorafenib and received sequential systemic therapy after regorafenib. These patients had significantly longer OS than those who were treated by the best supportive care or sub-optimal therapy (not reached versus 8.7 months [95% CI 5.8–11.7]; P

Background: There is no standard posttreatment for patients with advanced hepatocellular carcinoma (HCC) in whom lenvatinib therapy has failed. This study aimed to investigate rates of migration to posttreatment after lenvatinib and to explore candidates for second-line agents in the patients with failed lenvatinib therapy. Methods: We retrospectively collected data on patients with advanced HCC who received lenvatinib as the first-line agent in 7 institutions. Results: Overall survival and progression-free survival (PFS) of 178 patients who received lenvatinib as the first-line agent were 13.3 months (95% confidence interval [CI], 11.5–15.2) and 6.7 months (95% CI, 5.6–7.8), respectively. Sixty-nine of 151 patients (45.7%) who discontinued lenvatinib moved on to posttreatment. The migration rates from lenvatinib to the second-line agent and from the second-line agent to the third-line agent were 41.7 and 44.4%, respectively. Based on multivariate analysis, response to lenvatinib (complete or partial response according to modified RECIST) and discontinuation of lenvatinib due to radiological progression, as well as male were associated with a significantly higher probability of migration to posttreatment after lenvatinib. On the other hand, alpha-fetoprotein levels of 400 ng/mL or higher was correlated with a significantly lower probability of migration to posttreatment after lenvatinib. Of 63 patients who received second-line systemic therapy, 53 (84.2%) were administered sorafenib. PFS, objective response rate (ORR), and disease control rate (DCR) for sorafenib treatment were 1.8 months (95% CI, 0.6–3.0), 1.8%, and 20.8%, respectively. According to the Cox regression hazard model, Child-Pugh class B significantly contributed to shorter PFS. PFS, ORR, and DCR of 22 patients who received regorafenib after lenvatinib in any lines were 3.2 months (range, 1.5–4.9 months), 13.6%, and 36.3%, respectively. Similarly, PFS, ORR, and DCR of 17 patients who received regorafenib after lenvatinib in the third-line (after sorafenib) were 3.8 months (range, 1.1–6.5 months), 17.6%, and 41.2%, respectively. Conclusion: Sorafenib may not be a candidate for use as a posttreatment agent after lenvatinib, according to the results of the present study. Regorafenib has the potential to become an appropriate posttreatment agent after lenvatinib.

Background: The present study aimed to assess the efficacy and safety of lenvatinib and verify the possibility of lenvatinib for the expanded indication from the REFLECT trial in patients with advanced hepatocellular carcinoma (HCC) in real-world practice, primarily focusing on the population that was excluded in the REFLECT trial. Methods: We retrospectively collected data on patients with advanced HCC who were administered lenvatinib in 7 institutions in Japan. Results: Of 152 advanced HCC patients, 95 and 57 patients received lenvatinib in first-line and second- or later-line systemic therapies, respectively. The median progression-free survival in Child-Pugh class A patients was nearly equal between first- and second- or later-line therapies (5.2 months; 95% CI 3.7–6.9 for first line, 4.8 months; 95% CI 3.8–5.9 for second or later line, p = 0.933). According to the modified Response Evaluation Criteria in Solid Tumors, the objective response rate of 27 patients (18%) who showed a high burden of intrahepatic lesions (i.e., main portal vein and/or bile duct invasion or 50% or higher liver occupation) at baseline radiological assessment was 41% and similar with that of other population. The present study included 20 patients (13%) with Child-Pugh class B. These patients observed high frequency rates of liver function-related adverse events due to lenvatinib. The 8-week dose intensity of lenvatinib had a strong correlation with liver function according to both the Child-Pugh and albumin – bilirubin scores. Conclusion: Lenvatinib had potential benefits for patients with advanced HCC with second- or later-line therapies and a high burden of intrahepatic lesions. Dose modification should be paid increased attention among patients with poor liver function, such as Child-Pugh class B patients.

Background Conversion from sorafenib to regorafenib is primarily an evidence-based treatment strategy in patients with advanced hepatocellular carcinoma (HCC). This study aimed to assess the safety and efficacy of sequential therapy with sorafenib and regorafenib in patients with advanced HCC by analysis of outcomes in clinical practice with the aim to complement phase III findings. Methods The medical records of patients with advanced HCC receiving regorafenib were retrieved to collect data on sorafenib administration at seven Japanese institutions. Radiological responses and adverse events were evaluated using the Response Evaluation Criteria in Solid Tumors version 1.1 and the Common Terminology Criteria for Adverse Events version 4.0, respectively. Results Before March 2018, 44 patients were administered regorafenib for advanced HCC. The median sorafenib treatment duration was 8.4 months. The most common adverse events were similar to those reported by the RESORCE trial. The median overall survival (OS) was 17.3 months (95% confidence interval [CI] 11.4-22.9), and 17 of 37 patients (45.9%) discontinued regorafenib and received sequential systemic therapy after regorafenib. These patients had significantly longer OS than those who were treated by the best supportive care or sub-optimal therapy (not reached versus 8.7 months [95% CI 5.8-11.7]; P 0.001). Conclusion The results based on Japanese clinical practices verified the tolerability of regorafenib in advanced HCC. Major regorafenib-associated adverse events were similar to those related to sorafenib. OS was significantly longer than expected, which might be associated with the sequential systemic therapies after regorafenib, mainly lenvatinib.

278 Background: In clinical practice, the major disadvantage of lenvatinib to treat advanced hepatocellular carcinoma (HCC) is the lack of a posttreatment agent that has shown clear effectiveness. Thus, the establishment of second-line treatment after lenvatinib treatment failure is an urgent clinical issue to be addressed in systemic therapy in patients with advanced HCC. The study used real-world clinical data to explore candidate drugs that might be appropriate as second-line treatment after lenvatinib. Methods: We retrospectively reviewed the medical records of all patients with advanced HCC who received lenvatinib as the first-line agent in seven institutions in Japan between 23 March 2018 and 31 September 2019. Results: During the study period, 178 patients with advanced HCC received lenvatinib as first-line systemic therapy. At the time of lenvatinib administration, most patients were Eastern Cooperative Oncology Group Performance Status grade 0 or 1 (94.9%) and Child–Pugh class A (84.3%). According to the baseline radiological assessments, 25.3% and 36.0% of patients had macrovascular invasion and extrahepatic metastasis, respectively. Overall survival and progression-free survival (PFS) for lenvatinib treatment were 13.3 months (95% CI: 11.5–15.2) and 6.7 months (95% CI: 5.1–8.3), respectively. Of the 151 patients who discontinued lenvatinib, 71 (47.0%) converted to posttreatment. The conversion rates from lenvatinib to a second-line agent and from a second-line agent to a third-line agent were 41.4% and 42.4%, respectively. Based on multivariate analysis, lenvatinib response was defined as complete or partial according to the modified Response Evaluation Criteria in Solid Tumors (mRECIST). Lenvatinib discontinuation due to radiological progression, according to mRECIST, was associated with a significantly higher probability of conversion to posttreatment after lenvatinib. Of the 63 patients who received second-line systemic therapy, 53 (84.1%) were administered sorafenib, with a PFS, response rate (RR), and disease control rate (DCR) of 1.8 months (95% CI: 0.6–3.0), 1.8%, and 20.8%, respectively. According to the Cox proportional hazards regression model, lenvatinib discontinuation due to radiological progression, Child–Pugh class B, and intrahepatic tumor volume > 50% at the time of sorafenib administration significantly contributed to a shorter PFS. Of the 22 patients who received regorafenib after lenvatinib discontinuation, five cases were as second-line therapy, and 17 were as third-line therapy. PFS, RR, and DCR for regorafenib treatment were 3.2 months (range, 1.5–4.9 months), 13.6%, and 36.3%, respectively. Conclusions: Sorafenib was not considered a candidate posttreatment agent after lenvatinib, except in a limited number of patients who discontinued lenvatinib without radiological progression. Regorafenib is a potential posttreatment agent after lenvatinib.

Background and aims Some follow-up studies of large regenerative nodules (LRNs) and dysplastic nodules (DNs) were reported previously. However, the pre-malignant potentiality of LRNs has remained controversial up to now. No LRNs showed malignant transformation in our previous study. We aimed to evaluate the pre-malignant potentiality of LRNs and DNs with a greater number of cases and longer follow-up periods. Methods From 1982 to 2005, 1,500 consecutive nodular lesions up to 2 cm in diameter were subjected to US guided thin-needle biopsy in cirrhotic patients at Chiba University Hospital. Of these lesions, 68 LRNs in 60 cases and 20 DNs in 22 cases were followed up for more than 6 months without any anti-cancer therapy. The last US examination was in 2010. The total study period was 28 years. We analyzed the histological findings and the clinical data of all cases retrospectively. The outcome of the lesions was examined. Results The mean follow-up period was 38.9 (16–119) months in LRNs and 31.9 (6–101 months) in DNs. Rate of nodule enlargement was higher in DNs (8/24 nodules, 33 %) than LRNs (11/68 nodules, 16 %), (p = 0.0743, not significant). Rate of malignant transformation was also higher in DNs (10/24 nodules, 42 %) than LRNs (9/68 nodules, 13 %), (p = 0.0040, significant). The rate of disappearance in images was similar between LRNs and DNs. Conclusions We should recognize LRN as low risk pre-malignant lesions whereas DNs as high risk lesions.

Background Hypovascular nodules often occur together with hypervascular hepatocellular carcinoma (HCC). However, it remains controversial whether hypovascular nodules associated with hypervascular HCC have any prognostic value. This study evaluated the prognostic impact of hypovascular nodules co-existing with hypervascular HCC as diagnosed by computed tomography during arterial portography (CTAP) and computed tomography during hepatic arteriography (CTHA), which can sensitively capture the dynamic changes in blood flow through the portal vein and hepatic artery in patients with early stage HCC. Methods A total of 152 patients with hypervascular HCC (≤ 30 mm, ≤ 3 nodules), who underwent initial local ablation, were analyzed retrospectively. All patients received CTAP and CTHA prior to treatment. Overall survival (OS) was compared among group A (hypervascular HCC only, 107 patients) and group B (hypovascular nodules and hypervascular HCC, 45 patients). Results Among all hypovascular nodules, 81% (46 of 57) developed hypervascularization within the follow-up period. The 1- and 2-year hypervascularization rates were 17% and 51%, respectively. OS was significantly longer for group A than for group B (P < 0.001). A Cox proportional-hazards model identified the presence of hypovascular nodules concurrent with hypervascular HCC as an independent poor prognostic factor. Conclusion The prognosis of hypervascular HCC patients with hypovascular nodules detected during CTAP and CTHA is poor. Clinical HCC categories seem to be dissimilar between patients with and without hypovascular nodules.

Here, we describe the surgical treatment of a patient with hepatocellular carcinoma(HCC)with portal vein tumor thrombus (PVTT) after irradiation and transcatheter arterial chemoembolization (TACE). A 51-year-old man was being followed-up for HBV-related liver cirrhosis and HCC that was previously treated by radio-frequency ablation (RFA) and TACE. A follow up CT study revealed recurrence of HCC in segment 6 of the liver with PVTT extending to the right branch. As early recurrence was likely after resection and due to insufficient hepatic functional reserve, primary radiotherapy for PVTT was performed followed by TACE. After non-surgical treatment, a favorable tumor response was observed with no evidence of intrahepatic disease within the left lobe of the liver, and the volume of the future liver remnant increased, allowing us to perform splenectomy and right hemihepatectomy combined with portal vein resection/reconstruction.

A 63-year-old woman with abdominal pain was referred to our hospital. Her pancreatic enzymes were elevated, and an abdominal computed tomography (CT) scan showed an enlarged pancreas, consistent with pancreatitis, and gas collection containing an impacted stone adjacent to Vater's papilla. This finding raised the suspicion of a duodenal diverticulum. A subsequent ERCP showed a juxtapapillary duodenal diverticulum (JPDD) filled with calculi and pus. The pancreatitis improved with 2 weeks of conservative treatment. Subsequently, the patient underwent resection of the uterus and bilateral adnexa to remove a large ovarian cyst that was also identified on the admission CT scan. On the third postoperative day, she developed abdominal pain and vomiting. CT revealed small bowel obstruction caused by an enterolith expelled from JPDD. Enterotomy was performed to remove the stone. To our knowledge, only three similar cases have been previously reported in Japan.

To evaluate the therapeutic efficacy of percutaneous ethanol injection (PEI) for patients withor = 3 lesions of small (or = 3 cm diameter) hepatocellular carcinoma (HCC).PEI was applied to 270 patients with small HCC as the first-line treatment option during a 20-year period.(1) There was no treatment-related deaths, and only 2.2% of severe complications; (2) PEI induced a complete response of all HCCs according to CT evaluation performed within one month after the procedure, and the local recurrence rate at 3 years was 10%; (3) the overall 3- and 5-year survival rates after treatment were 81.6 and 60.3%, respectively, but the rates were higher, 87.3 and 78.3%, in Child A patients with a solitary tumoror = 2 cm in diameter; (4) factors significantly influencing survival were liver function (P = 0.0033) and serum alpha-fetoprotein level (P = 0.0014), and (5) the recurrence rate at remote sites in the liver was lower in patients with HCCor = 2 cm (P = 0.0395) and in those with a solitary HCC (P0.0001) according to Cox's proportional hazard model. (6) Radiofrequency ablation would not have been performed in approximately 25% of these patients.PEI is considered a reliable treatment for small HCC in terms of safety and efficacy.

We administered trientine hydrochloride, a drug used in the treatment of Wilson's disease, to patients with hepatocellular carcinoma after radical treatment with percutaneous ethanol injection or radiofrequency ablation, and examined its effect on the reduction of liver-tissue copper content. We enrolled 24 patients with 3 or fewer primary lesions of Child class A or B hepatocellular carcinoma with diameters of 3 cm or less who had undergone radical treatment with percutaneous ethanol injection or radiofrequency ablation. Trientine hydrochloride was orally administered in a single daily dose of 250 mg to 12 patients before a meal (at fasting, group 1) or at a total daily dosage of 750 mg, divided into 3 doses, to 12 patients (group 2). This study was a randomized between-groups comparative study of 12 weeks' duration. We used the particle-induced x-ray-emission method to determine liver-tissue mineral content. Urine copper and serum mineral levels were also measured, and transaminase levels were examined. Liver-tissue copper content decreased significantly, to 160.1 microg/g dry weight, after treatment, compared with the pretreatment level of 306.8 microg/g dry weight (P

The proto-oncogene Bcl6 and its family gene, BAZF, encode a sequence-specific transcriptional repressor which contains the BTB/POZ domain in NH2-terminal region and zinc finger motifs in COOH-terminal region. The BTB/POZ domain and the middle portion of Bcl6 and BAZF are known to display transrepressor activity. Since we have identified the identical 17-amino acid (aa) sequence in the middle portion of Bcl6 and BAZF, the 17aa region may be another repressive domain of the middle portion. The reporter gene assay indicates that the 27aa sequence including the 17aa region recruits histone deacetylases to express transrepressor activity. Furthermore, overexpression of Bcl6 or Bcl6(POZ−) (Bcl6 deleted with the BTB/POZ domain) induced apoptosis in NIH3T3 cells, and the apoptosis was inhibited by the addition of histone deacetylase inhibitor in the culture. However, apoptosis was not induced in NIH3T3 cells by overexpression of Bcl6(POZ−) deleted with the 17aa region. These results indicate that the 17aa region in the middle portion of Bcl6 is a functional domain of transrepressor activity and is responsible for inducibility of apoptosis in NIH3T3 cells.

BAZF, a family member of Bcl6, can function as a sequence-specific transcriptional repressor. We determined BAZF-binding DNA sequence. The consensus binding sequence (CBS) of BAZF is almost the same as those of Bcl6 previously described. Three nucleotides of T, G and A at position 6, 8, and 9 in the CBS (5'-ATTCCTAGAAAG-3') are important nucleotides for binding of both BAZF and Bcl6. Since a part (5'-TTC-CTA-GAA-3') of the CBS resembled the sequence motif (5'-TTC-(N3-4)-GAA-3') bound by STAT factors, BAZF and Bcl6 can bind to the CD23b-STAT6-binding sequence (5'-TTTC-TTA-GAAAT-3'), the immunoglobulin germline epsilon-STAT6-binding sequence (5'-CTTC-CCAA-GAAC-3'), and the IL4-STAT6-binding sequence (5'-TTTC-CCA-GAAAA-3') with weak affinity. However, a mutation of C nucleotide to T nucleotide in the IL4-STAT6-binding sequence (5'-TTTC-CTA-GAAAA-3') strongly increased the binding activity of BAZF and Bcl6. These results suggest that BAZF and Bcl6 can repress some of STAT-induced transcription by binding to DNA sequences recognized by STAT factors.

The Bcl6 gene has been identified from the chromosomal translocation breakpoint in B cell lymphomas, and its products are expressed highly in germinal center (GC) B cells. To investigate the function of Bcl6 in lymphocytes, we have generated RAG1-deficient mice reconstituted with bone marrow cells from Bcl6-deficient mice (Bcl6−/−RM). Lymphogenesis in primary lymphoid tissues of Bcl6−/−RM is normal, and Bcl6−/−RM produced control levels of primary IgG1 antibodies specific to T cell–dependent antigens. However, GCs were not found in these mice. This defect was mainly due to the abnormalities of B cells. Therefore, Bcl6 is essential for the differentiation of GC B cells.

Little is known about portal vein thrombosis (PVT) after radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC). We aimed to determine the incidence, background, and natural history of RFA-related PVT.This is a retrospective study of 317 patients (219 males and 98 females) with HCC treated by RFA. Clinical data were compared between patients with and without PVT detected by ultrasound/CT. The median follow-up period after RFA was 15.8 months.PVT was detected in 6 (1.9 %) of 317 patients, 6 (0.8 %) of 802 treatments for HCC, and 6 (0.6 %) of 964 sessions of RFA. Body mass index was significantly higher in patients with PVT (26.9 ± 3.1 kg/m(2)) than in those without (22.9 ± 3.5 kg/m(2), p = 0.0075). PVT was significantly more frequent in RFA for the left lobe of the liver (2.7 %) than for the other sites (0 %, p 0.0001). Five of the six patients received no treatment for PVT, with natural outcomes of disappearance in one patient, improvement in one patient, and unchanged appearance in three patients. Anticoagulation was applied in the one remaining patient and resulted in a successful recanalization. In the six patients, there was no significant difference in hepatic functional reserve between baseline and time of detection of PVT.These results indicated that a high body mass index and RFA for HCC in the left lobe might be significant risk factors for PVT and that RFA-related PVT was rarely progressive with little influence on liver function.

We analyzed the expression of the BCL6 gene in mouse tissues by in situ hybridization. The expression was strong in the upper layer but undetectable in the basal layer of epidermis from adult mice. When human keratinocytes were cultured with a high concentration of calcium ion, these cells stopped their proliferation and differentiated to their terminal stage. In these keratinocytes, BCL6 expression was induced after stimulation and progressively up-regulated. The kinetics was very similar to that of a cyclin dependent kinase inhibitor p21sdil/cip1/WAF1 in these cells. These results suggest that BCL6 plays a role in keratinocytes at terminal differentiation stage.

Purpose To assess the value of gadoxetic acid-enhanced magnetic resonance imaging (MRI) for the pre-therapeutic detection of hepatocellular carcinoma (HCC) using receiver operating characteristic (ROC) analysis with the combination of computed tomography (CT) arterial portography and CT hepatic arteriography (CTAP/CTHA). Materials and Methods A total of 54 consecutive patients with 87 nodular HCCs were retrospectively analyzed. All HCC nodules were confirmed pathologically. Three blinded readers independently reviewed 432 hepatic segments, including 78 segments with 87 HCCs. Each reader read two sets of images: Set 1, CTAP/CTHA; Set 2, gadoxetic acid-enhanced MRI including a gradient dual-echo sequence and diffusion-weighted imaging (DWI). The ROC method was used to analyze the results. The sensitivity, specificity, positive predictive value, negative predictive value and sensitivity according to tumor size were evaluated. Results For each reader, the area under the curve was significantly higher for Set 2 than for Set 1. The mean area under the curve was also significantly greater for Set 2 than for Set 1 (area under the curve, 0.98 vs. 0.93; P = .0009). The sensitivity was significantly higher for Set 2 than for Set 1 for all three readers ( P = .012, .013 and .039, respectively). The difference in the specificity, positive predictive values and negative predictive values of the two modalities for each reader was not significant ( P > .05). Conclusion Gadoxetic acid-enhanced MRI including a gradient dual-echo sequence and DWI is recommended for the pre-therapeutic evaluation of patients with HCC.

This prospective study was performed in 179 hepatocellular carcinoma (HCC) lesions treated by radio-frequency ablation (RFA) to explore the clinical outcome of "linear enhancement" on contrast-enhanced sonogram. Thirty-three lesions (18.4%) showed linear enhancement, a linear-shaped positive enhancement in the RFA-treated area. Seventeen of them were followed up with no treatment (remaining 16; dropout in eight, additional RFA in six and ineffective treatment in two) and three lesions (3/17, 17.6%) showed local tumor progression corresponding to linear enhancement at 7, 14, 19 months after RFA. Although there was no significant difference in local recurrence rate between the lesions with (3/17) and without linear enhancement (10/35), local tumor progression inside the ablation zone occurred only in the lesions with linear enhancement. In conclusion, linear enhancement inside the RFA-treated area should be followed up within 7 months because it has a risk of local tumor progression. Histology of linear enhancement and its influence on distant recurrence remain to be solved.

Purpose To elucidate the changes in tumor vascularity and microbubble accumulation on contrast-enhanced sonograms, in relation to the dedifferentiation of hepatocellular carcinoma (HCC). Materials and methods This prospective study enrolled 10 patients with histologically proven HCC (14.4–39.0 mm, 26.1 ± 7.4) showing nodule-in-nodule appearance upon contrast-enhanced computed tomography. Contrast-enhanced ultrasound was performed by harmonic imaging under a low mechanical index (0.22–0.25) during the vascular phase (agent injection to 1 min) and late phase (15 min) following the injection of Sonazoid™ (0.0075 ml/kg). Contrast enhancement in the inner and outer nodules was assessed in comparison with that in adjacent liver parenchyma as hyper-, iso-, or hypo-enhanced. Results Vascular-phase enhancement of all 10 inner nodules was hyper-enhanced, and that of outer nodules was hyper-enhanced in 3, iso-enhanced in 2, and hypo-enhanced in 5. Late-phase enhancement of inner nodules was hypo-enhanced in 8 and iso-enhanced in 2. Furthermore, late-phase enhancement of outer nodules was iso-enhanced in the 7 lesions that showed iso- or hypo-enhancement in the vascular phase, and hypo-enhanced in the 3 with hyper-enhancement in the vascular phase. Late-phase hypo-enhancement was significantly more frequent in the nodules showing early-phase hyper-enhancement (11/13) than in the nodules showing early-phase iso- or hypo-enhancement (0/7) in both the inner and outer nodules. Conclusion Dedifferentiation of HCC may be accompanied by changes in tumor vascularity prior to a reduction in microbubble accumulation. Observation of the vascular phase may be more useful than late-phase imaging for the early recognition of HCC dedifferentiation when using contrast-enhanced ultrasound with Sonazoid.

Background/Aims: The aim was to examine the efficacy of contrast-enhanced ultrasound (US) with Sonazoid™ to demonstrate ultrasonically unrecognizable hypervascular hepatocellular carcinoma (HCC) and apply percutaneous US-guided treatments. Methods: The subjects of this prospective study were 44 cirrhotic patients with 55 hypervascular lesions (12.7±4.5 mm) found by contrast-enhanced computed tomography but unrecognized by non-contrast US. Contrast-enhanced US was performed to demonstrate these hepatic lesions after an intravenous injection of Sonazoid™ (0.0075 ml/kg). The sonograms in both the early phase (for 1 min after injection) and the late phase (5–10 min after) were taken in the harmonic imaging mode under a low mechanical index (0.24–0.3). Results: Fifty-three lesions were demonstrated by contrast-enhanced US, 52 with positive enhancement in the early phase and 44 with negative enhancement in the late phase. Percutaneous US-guided treatments were successfully performed for 42 lesions (ethanol injection in 20 and radiofrequency ablation in 22) in 32 patients with reference to contrast-enhanced US findings. Six patients were treated by transarterial chemoembolization alone because they had more than three lesions in the liver. In the remaining seven lesions in six patients, six were diagnosed as non-HCC lesions: five with vascular abnormalities such as arterioportal or arteriovenous communication and the other one with benign lesion in alcoholic liver disease. These six lesions and one HCC lesion with severe liver damage were followed up without any treatment. Conclusions: As the detectability of ultrasonically unrecognizable hypervascular HCC improved by contrast-enhanced US with Sonazoid™, a wider application of percutaneous US-guided treatments may be possible.

In the study carried out in goats, we used the JC200 focused ultrasound tumor therapeutic system (Chongqing Haifu Tech Co., Ltd, China). The therapeutic ultrasound energy is produced by a transducer with a focal length of 160mm, at a frequency of 0.8MHz. The animals (n=6) were divided into a control group (n=3) and an experimental group subjected to costectomy (n=3). Costectomy was performed 1 week before HIFU. There was no difference in the coagulation volume between the two groups. Skin burns accompanied with reddish color and focal edema were observed in two goats. There were no other complications. In the clinical study, HIFU was applied in patients with with ⩽ 3 lesions of liver carcinoma ⩽ 4cm in diameter. The complications and anti‐tumor effects on liver carcinomas should be evaluated. Tumor ablation was complete in 5 of 6 patients. There were no complications such as skin burns and local pain. HIFU did not influence blood chemical findings.

The BAZF gene has recently been identified as a novel homologue of the BCL6 oncogene. Here we cloned the human BAZF gene using murine BAZF as a probe. The predicted amino acid sequence was 91% identical to that of murine BAZF. The BTB/POZ and zinc finger domains were almost completely conserved between human and murine BAZF. Fluorescence in situ hybridization analysis revealed that the human BAZF gene is located on chromosome 17p13.1. Although expression of human BAZF mRNA was ubiquitously detected in human tissues, abundant expression was detected in heart and placenta. BAZF mRNA was expressed in some immature B cell lines and erythroleukemia cell lines. The expression in a human erythroleukemia cell line, HEL cells, was upregulated during megakaryocytic differentiation induced by 12-O-tetradecanoyl-phorbol-13-acetate. These expression patterns of BAZF mRNA suggest that BAZF may regulate differentiation in stages or lineages that are different from those regulated by BCL6.

Objective: The Bcl6 gene encodes a sequence-specific transcriptional repressor and is ubiquitously expressed in adult murine tissues including heart muscle. The objective of this study was to examine the role of Bcl6 in cardiac myocytes. Method: We developed Bcl6 -deficient (Bcl6−/−) mice and histologically examined hearts from these mice. Results: Massive myocarditis with eosinophilic infiltration occurred in Bcl6−/− mice after 4–6 weeks of age. Since expression of the Bcl6 gene was induced in normal cardiac myocytes after 2 weeks of age and thereafter detected through adulthood, loss of Bcl6 in mature cardiac myocytes may be related to the induction of eosinophilic myocarditis. To examine the effects of eosinophils from Bcl6−/− mice on normal hearts, bone marrow cells from Bcl6−/− mice were adoptively transferred into sublethally irradiated RAG1-deficient mice. Although massive eosinophilic infiltration was detected in conjunctivas and spleens from the chimeric mice, myocarditis was never observed. Electron microscopic analysis of cardiac myocytes from Bcl6−/− mice revealed a spectrum of degenerative changes prior to eosinophilic infiltration. Conclusion: Bcl6 may not be essential for the maturation of cardiac myocytes but may play a role in protecting mature cardiac myocytes from eosinophilic inflammation.

The BCL6 gene, which has been identified from the chromosomal translocation breakpoint in B-cell lymphomas, functions as a sequence-specific transcriptional repressor. We cloned a novel Bcl6-homologous gene, BAZF (encoding Bcl6-associated zinc finger protein). The predicted amino acid sequence of BAZF indicated that the BTB/POZ domain and the five repeats of the Kruppel-like zinc finger motif are located in the NH2-terminal region and the COOH-terminal region, respectively. BAZF associated with Bcl6 at the BTB/POZ domain and localized in the nucleus. Since zinc finger motifs of BAZF were 94% identical to those of Bcl6 at the amino acid level, BAZF bound specifically to the DNA-binding sequence of Bcl6 and functioned as a transcriptional repressor. The repressor activity was associated with both the BTB/POZ domain and the middle portion of BAZF. The 17-amino-acid sequence in the middle portion was completely conserved between BAZF and Bcl6, and the conserved region was critical for the repressor activity. Expression of BAZF mRNA, like that of Bcl6 mRNA, was induced in activated lymphocytes as an immediate-early gene. Therefore, the biochemical character of BAZF is similar to that of Bcl6 although the tissue expression pattern of BAZF differs from that of Bcl6. This is apparently the first report of a gene family whose members encode zinc finger proteins with the BTB/POZ domain.