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Background: Hepatocellular carcinoma (HCC) is more likely to occur in patients with a history of Fontan surgery, possibly due to long-term liver congestion. Proton beam therapy (PBT) may be effective for HCC that develops after Fontan surgery. Methods: Six lesions in 5 patients (3 females, 2 males) received PBT. The median age of the patients was 33 (range 21 - 42) years, and the median age at the time of the Fontan procedure was 6 (5 - 13) years. Four patients had multiple HCC at the time of PBT. The median tumor size was 57 (22 - 80) mm and 4 patients were classified as Child-Pugh B. Two patients received transcatheter arterial chemoembolization before PBT. The schedule of PBT was 66 Gy (RBE) in 10 fractions for 2 lesions, 72.6 Gy (RBE) in 22 fractions for 2 lesions, and 74 GyE (RBE) in 37 fractions for 2 lesions. Results: The median follow-up period was 31 (10 - 46) months, and the numbers of survivors, deaths from primary diseases, and deaths from other diseases were 3, 1, and 1, respectively. There were no local recurrences, one intrahepatic metastasis, one lung metastasis, and one intrathoracic metastasis. Conclusion: Although experiences on a small number of patients cannot conclude things, we believe that PBT can be a reasonable choice of radical treatment for HCC occurring after the Fontan procedure.

A 69-year-old woman who had a history of chronic hepatitis C, autoimmune hemolytic anemia and myelodysplastic syndrome was treated with sorafenib at a daily dose of 400 mg for HCC with multiple lung metastases. Nonetheless, elevated serum tumor markers further increased (alpha fetoprotein from 121,100 to 348,660 ng/ml and protein induced by vitamin K absence/antagonist-II from 3435 to 29,357 mAU/ml), and lung metastatic lesions on chest X-ray showed no improvement after 2 months of sorafenib treatment. Sorafenib was discontinued because of adverse events with diarrhea, fatigue, and severe anemia due to bleeding from stomach telangiectasia. Hand-foot syndrome was mild. Thereafter, the tumor markers rapidly decreased to almost normal range, and the lung and liver tumors markedly shrunk and disappeared without any other cancer treatments. Her tumors remained in complete remission for 17 months until an intrahepatic recurrence occurred. This unique course of metastatic HCC indicated that antitumor mechanisms other than the direct anticancer effect of sorafenib contributed to tumor shrinkage.

Pancreatic-pleural fistula is a rare but severe complication with pancreatitis. A 50-year old man with heavy alcoholic history was transferred to our hospital due to pancreatic pleural effusion with diffuse pancreatic swelling. MRCP revealed two stenotic parts of main pancreatic duct. We inserted a pancreatic stent, and pleural effusion was improved. However, diffuse pancreatic swelling still remained for 3 months. Autoimmune pancreatitis was suspected because of morphologic appearance and high serum levels of IgG4. We confirmed his illness as Type 1 autoimmune pancreatitis pathologically by EUS-FNA and started steroid administration. Diffuse pancreatic swelling was improved immediately. Pancreatic-pleural fistula did not relapse after removing the pancreatic stent and tapering steroid. This is a first report for pancreatic-pleural fistula caused by autoimmune pancreatitis and successfully treated with pancreatic drainage and steroid.

Percutaneous transhepatic obliteration (PTO) can facilitate antegrade embolization of variceal veins. We herein report three patients who underwent percutaneous transhepatic sclerotherapy (PTS) or percutaneous transportal outflow-vessel-occluded sclerotherapy (PTOS) for isolated gastric varices. PTS was performed in Cases 1 and 2, and PTOS was performed in Case 3. Technical success was achieved in all patients without a decline in liver function; however, lack of a therapeutic benefit with rupture of esophageal varices occurred in Case 3. Case 3 had a history of pylorus gastrectomy plus Billroth-I reconstruction for gastric cancer and multiple feeding veins existed. PTO-related procedures are good treatment options for isolated gastric varices, but clinicians should be aware of the risk of treatment failure, especially the cases which have multiple feeding veins.

In radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC), it is difficult to assess the ablative margin (AM) precisely by comparing pre- and post-RFA CT images. We prospectively studied the AMs using magnetic resonance imaging (MRI) with pre-administered superparamagnetic iron oxide (SPIO). SPIO is safe for kidney disease patients. Hepatocellular carcinoma patients were treated with RFA within 8 h of SPIO administration. On T2*-weighted MRI performed 4–7 days later, AM was visualized as a hypointense rim. The ablation status was classified as AM(+) if the rim completely surrounded the tumor, AM(0) if the rim was partly discontinuous without tumor protrusion, and AM(−) if the rim was partly discontinuous with tumor protrusion. The minimal thickness of AM was measured. AM(−) tumors were re-treated consecutively. In total, 85 HCCs ablated in 76 patients were evaluated. The local recurrence rate at 3 years was 2% for AM(+) tumors and 34% for AM(0) tumors (p

A 70-year-old woman was referred to our department due to a solitary mediastinal tumor which gradually grew near the site of anastomosis for 8 years after radical surgery of esophageal squamous cell carcinoma. It was difficult to distinguish the lymph node recurrence of esophageal cancer from another tumor of unknown primary origin. Endoscopic ultrasound-guided fine-needle aspiration was performed, and the tumor was diagnosed to be neuroendocrine carcinoma. She received concurrent chemoradiotherapy with etoposide plus cisplatin. After the completion of chemoradiotherapy, the tumor disappeared. A solitary growing tumor which develops after radical resection of cancer would be better to be examined histologically in order to make an accurate diagnosis and select the most appropriate treatment.

A 43-year-old man was admitted to a local hospital because of acute left abdominal pain. Chronic alcoholic pancreatitis and a 10-cm pancreatic pseudocyst in the tail of the pancreas had been found 5 years previously. He had not stopped drinking alcohol since then. On admission, laboratory tests revealed severe anemia, and contrast-enhanced computed tomography showed extravasation in the pancreatic pseudocyst. The spleen was retracted by the pancreatic pseudocyst, and its configuration was indistinct. The patient was diagnosed with acute bleeding within the pancreatic pseudocyst and splenic rupture. He was transferred to our university hospital on an emergency basis. Abdominal angiography of the splenic artery was immediately performed, but the bleeding point was not found. Although the bleeding stopped spontaneously, an infection of the pancreatic pseudocyst and a splenic hematoma subsequently developed. Endoscopic ultrasound-guided pseudocyst drainage was performed. The infection improved after the drainage, and the size of the pancreatic pseudocyst and splenic hematoma decreased. Five months later, the pancreatic pseudocyst had almost disappeared, and the splenic hematoma was even smaller. We herein report a rare case of splenic rupture caused by a pancreatic pseudocyst. Although the patient’s condition became complicated by severe infection, treatment by endoscopic ultrasound-guided drainage was successful.

Here we report a case of long-term survival with own liver in the patient of biliary atresia (BA) who developed hepatocellular carcinoma (HCC). The patient was a 34-year-old man. He underwent a portal jejunostomy with a diagnosis of BA (IIIb1ν) on the 94th day after birth, with a favorable post-operative course. Contrast-enhanced CT upon admission for cholangitis at the age of 34 suspected HCC, with an AFP level of 1.3 ng/ml and increased PIVKAII to 1,199 mAU/ml. He was diagnosed with HCC on MRI, and the tumor embolus had spread to the left branch of the portal vein; thus, resection and transplantation were considered contraindication. Proton therapy was performed, but he died 11 months after the detection of HCC. To date, 26 cases of HCC including this one have been reported, of which 20 were those in minors. Many of the patients with early onset have poor prognosis such as poor reduction of jaundice, while many of those with adult onset have relatively favorable prognosis as in this case; therefore, it was suggested that the progression of cholestatic cirrhosis is associated with carcinogenesis.

Advanced liver cancers and biliary cancers represent diseases with dismal prognosis because of frequent local invasion and metastasis. Effective therapeutic agents for these cancers have not been established. Oncolytic viruses (OVs) constitute a novel class of promising, selective anticancer agents and recent studies have elucidated their unique features. Moreover, clinical trials are demonstrating promising results. Numerous OVs are being tested in preclinical models of hepatocellular carcinoma (HCC). The lead agent Pexa-Vec (pexastimogene devacirepvec, JX-594), a recombinant Wyeth strain vaccinia virus, has demonstrated preliminary evidence of safety and efficacy for HCC in clinical trials. Few other OVs have entered clinical testing. Relatively few preclinical studies and clinical trials exist for biliary cancers. In this review, we introduce various approaches using OVs to treat the intractable hepatobiliary cancers.

Long-term efficacy of proton beam therapy (PBT) remains unclear for patients with previously untreated hepatocellular carcinoma (HCC). We aimed to study the long-term outcomes of PBT according to Barcelona Clinic Liver Cancer (BCLC) staging classifications in patients with previously untreated HCC. The major eligibility criteria of this observational study were an Eastern Cooperative Oncology Group performance status (PS) 0-2, Child-Pugh grade A or B, previously untreated HCC covered within an irradiation field, and no massive ascites. A total of 66.0-77.0 GyE was administered in 10-35 fractions. Local tumor control (LTC), defined as no progression in the irradiated field, progression-free survival (PFS), and overall survival (OS) were assessed according to BCLC staging. From 2002 to 2009 at our institution, 129 patients were eligible. The 5-year LTC, PFS, and OS rates were 94%, 28%, and 69% for patients with 0/A stage disease (n=9/21), 87%, 23%, and 66% for patients with B stage disease (n=34), and 75%, 9%, and 25% for patients with C stage disease (n=65), respectively. The 5-year LTC and OS rates of 15 patients with tumor thrombi in major vessels were 90% and 34%, respectively. Multivariate analyses revealed that PS (0 versus 1-2) was a significant prognostic factor for OS. No grade 3 or higher adverse effects were observed. PBT showed favorable long-term efficacies with mild adverse effects in BCLC stage 0 to C, and can be an alternative treatment for localized HCC especially when accompanied with tumor thrombi. This study was registered with UMIN Clinical Trials Registry (UMIN0000025342). This article is protected by copyright. All rights reserved.

Although transcatheter arterial chemoembolization is one of the established treatments for hepatocellular carcinoma (HCC), it is difficult to treat HCCs with prominent arterioportal (AP) shunts because anticancer drugs and embolic materials migrate into the non-tumorous liver through the AP shunts and may cause liver infarction. We developed a novel method of balloon-assisted chemoembolization using a micro-balloon catheter alongside a microcatheter simultaneously inserted through a single 4.5-Fr guiding sheath, comprising proximal chemoembolization with distal arterial balloon occlusion. We applied this method to treat an HCC with a prominent distal AP shunt induced by previous proton beam therapy and achieved successful chemoembolization without non-tumorous liver infarction under temporal balloon occlusion of a distal AP shunt.

Objectives:We aimed to identify dynamic CT features that can be used for prediction of local recurrence of hepatocellular carcinoma (HCC) after proton beam therapy (PBT).Methods:We retrospectively retrieved CT scans of patients with PBT-treated HCC, taken between January 2004 and December 2016. 17 recurrent lesions and 34 non-recurrent lesions were retrieved. The attenuation difference between irradiated tumor and irradiated parenchyma (ADHCC-IP) was compared in the two groups by using the Mann–Whitney U test. Cut-off value of ADHCC-IPwas estimated by using the Youden index.Results:The follow-up time after PBT initiation ranged from 374 to 2402 days (median, 1069 days) in recurrent lesions, and 418 to 2923 days (median, 1091.5 days) in non-recurrent lesions (p = 0.892). The time until appearance of local recurrence after PBT initiation ranged from 189 to 2270 days (median, 497 days). ADHCC-IPof recurrent lesions [mean, −21.8 Hounsfield units (HU); from −95 to −31 HU] was significantly greater than that of non-recurrent lesions (mean, −51.7 HU; from −117 to −12 HU) at 1–2 years in portal venous phase (p = 0.039). 5-year local tumor control rates were 0.93 and 0.56 in lesions with ADHCC-IPat 1–2 years in PVP < −55 and ≥ −55 HU, respectively.Conclusion:The attenuation difference between irradiated HCC and irradiated liver parenchyma in portal venous phase at 1-2 years after PBT can predict long-term local recurrence of HCC after treatment.Advances in knowledge:We identified a cut-off value for contrast enhancement of HCC after PBT that could predict future local recurrence.

Background The effectiveness of proton beam therapy (PBT) as initial treatment for patients with unresectable intrahepatic cholangiocarcinoma (ICC) is unclear, particularly as related to ICC histological subtypes. We performed this study to address this gap in knowledge. Methods Thirty-seven patients with unresectable ICC who underwent PBT as their initial treatment were evaluated. Twenty-seven patients had Child-Pugh class A liver function, 11 exhibited jaundice, and 10 had multiple tumors. Nineteen, 7, and 11 tumors were classified as mass forming (MF), periductal infiltrating (PI), and intraductal growth (IG) types, respectively, based on gross appearance in imaging studies. Patients were classified into the curative group (n = 25) and palliative group (n = 12) depending on whether the planning target volume covered all the macroscopic tumors. Results The 1- and 2-year overall survival rates were 60.3, and 41.4%, respectively; the median survival time (MST) was 15 months for all patients. The MSTs for curative and palliative groups were 25 and 7 months, respectively. Curative treatment and adjuvant chemotherapy significantly improved overall survival, while the presence of periductal infiltrating type tumors was a negative prognostic factor. In the curative group, the 1- and 2-year local control rates were 100 and 71.5%, respectively, while the 1-, and 2-year progression-free survival rates were 58.5, and 37.6%, respectively. No severe acute toxicities were observed. Three patients experienced grade 3 biliary tract infection, although it was unclear whether this was radiotherapy-related. Conclusion PBT may yield to improve survival and local tumor control among patients with unresectable ICC.

Background and Aim Treatment for unresectable intrahepatic cholangiocarcinoma (ICC) has not been established. The aim of the study was to evaluate the outcome of proton beam therapy (PBT) for patients with unresectable ICC. Methods Up to 2010, 20 patients (11 males, 9 females, median age 63 years old) with unresectable ICC (two, seven, seven, and four in stages II, IIIA, IIIC, and IV, respectively) were treated with PBT. The largest dimensions of the tumors ranged from 15 to 140 mm (median: 50 mm). The intrahepatic region and lymph nodes received median total proton doses of 72.6 GyE in 22 fractions and 56.1 GyE in 17 fractions, respectively. Four patients received concurrent chemotherapy (tegafur, gimeracil, and oteracil; TS-1) during PBT. Twelve patients were treated curatively, and eight were treated palliatively because tumors were present outside the irradiation field. Results In the curative group, nine tumors within the irradiated field were controlled in follow-up of 8.6–62.6 months (median: 20.8 months). Median survival rates in the curative and palliative groups were 27.5 and 9.6 months, respectively, and overall 1- and 3-year survival rates were 82% and 38%, and 50% and 0%, respectively. Eight patients survived for > 2 years, and there was no distant metastasis in five of these patients after 2 years. No severe side-effects occurred. Conclusions The results suggest that long-term survival can be achieved using PBT for patients with unresectable ICC without distant metastasis. Further studies are required to determine the optimal treatment schedule and best combination of PBT and chemotherapy.

Hepatitis E caused by hepatitis E virus (HEV) is a serious public health concern in developing countries where HEV is mainly transmitted through contaminated water. Recently, in industrialized countries, autochthonous hepatitis E, a porcine zoonosis, has been increasingly recognized. In Japan, the number of national notifications of acute hepatitis E has increased since the introduction of anti-HEV IgA antibody measurement, covered by the national health insurance program, in 2011. In the past three years, we examined five patients of acute hepatitis or acute-on-chronic liver failure caused by HEV infection who presented various clinical courses in the southern area of Ibaraki prefecture in Japan. Of these patients, 78-year-old and 63-year-old male patients presented acute hepatitis E and recovered by only bed rest. The latter patient had a history of consuming grilled or undercooked pork and shellfish prior to the onset of hepatitis E. Among the five patients examined, the infection route was detected only in this patient. Of note, a 65-year-old female patient presented severe hepatitis associated with painless thyroiditis. The patient was diagnosed with probable autoimmune hepatitis and was successfully treated with prednisolone (40 mg/day). Lastly, 58-year-old and 62-year-old male patients, both of whom had a history of diabetes mellitus and alcoholic liver disease, developed acute-on-chronic liver failure, and the latter patient with pre-existing liver cirrhosis died due to liver failure. Thus, patients with clinical HEV infection who display multiple underlying diseases can develop acute-on-chronic liver failure. In conclusion, HEV infection manifests the diverse clinical courses.

The Child-Pugh score is often used to judge the outcome of radiotherapy for hepatocellular carcinoma (HCC). The retention rate of indocyanine green 15 min after administration (ICG R15) can also be used to predict prognosis after liver resection. We evaluated the utility of ICG R15 for prediction of outcomes after proton beam therapy (PBT) for HCC.A retrospective evaluation was performed in 250 patients who received PBT between 2002 and 2007. The patients (178 males and 72 females) had a median age of 71 years (range: 43-88). Child-Pugh categories were A (score 5-6), B (7-9), and C (10-15) in 197, 51, and 2 patients, respectively. ICG scores were 0-10, 10-20, 20-30, 30-40 and ⩾40 in 27, 99, 59, 28 and 37 patients, respectively; including 26, 92, 45, 16 and 18 Child-Pugh A patients and 1, 8, 14, 11, and 17 Child-Pugh B patients, respectively. Survival times from the start of PBT were compared between Child-Pugh A and B patients, and among each ICG group.The median survival times were 61 months (95% CI: 50-72 months) in all patients, and 64 and 20 months in Child-Pugh A and B patients, respectively (p=0.001), The 3-year survival rates were 72%, 72%, 75%, 63%, and 26% in patients with ICG scores of 0-10, 10-20, 20-30, 30-40, and ⩾40 (p=0.001); 70%, 75%, 77%, 65%, and 38% in these respective groups in Child-Pugh A patients (p=0.02); and 100%, 57%, 67%, 36%, and 14% in Child-Pugh B patients (p=0.173, not significant). Multivariate analysis showed that low ICG R15 and the absence of portal vein tumor thrombus were associated with good survival.Pretreatment ICG R15 is a useful prognostic factor for prediction of outcome of PBT in HCC patients, especially in those with Child-Pugh A liver function.

Adenocarcinomas arising from the ectopic pancreas in the gastrointestinal wall are rarely described in the literature. In addition, obtaining an accurate preoperative diagnosis is difficult in most cases because these adenocarcinomas occur primarily in the submucosal layer and form submucosal tumors. Endoscopic ultrasonography-guided fine-needle aspiration and endoscopic mucosal resection with a transparent plastic cap-fitted panendoscope followed by a biopsy are useful for histological typing and making the differential diagnosis of adenocarcinoma, gastrointestinal stromal tumor, malignant lymphoma or other. These procedures represent the first step toward diagnosing ectopic pancreatic adenocarcinoma. We herein report two such cases with a review of the pertinent literature.

Background: Sorafenib has been used in the treatment of advanced hepatocellular carcinoma (HCC) and renal cell carcinoma (RCC). Sorafenib-associated organ reduction have been reported on imaging, such as thyroid, pancreas and muscle, but there has been no research on prostate volume reduction (PVR). Methods: We retrospectively analyzed 26 patients (twenty with HCC and six patients with RCC) who underwent sorafenib therapy for 31 to 1225 days (median, 100 days). PVR was estimated by two independent readers using CT volumetry. Results: The sum of all prostate volumes measured by reader 1 was 24.2 ± 13.8 cm3 on the baseline CT and 20.4 ± 10.6 cm3 on the follow-up CT (p < 0.001), and that measured by reader 2 was 22.3 ± 13.9 cm3 on the baseline CT and 19.2 ± 10.6 cm3 on the follow-up CT (p < 0.001). The concordance correlation coefficient for the prostate volume measured by the two readers was 0.95 on the baseline CT scans and 0.94 on the follow-up CT scans. Sorafenib-associated PVR demonstrated slight dependence to the exposure time (r = –0.23). One patient with benign prostatic hyperplasia (BPH) showed PVR (from 80.4 to 61.5 cm3 [reader 1]; 83.4 to 61.6 cm3 [reader 2]) after sorafenib administration. Sorafenib-associated PVR occurred in patients both with and without underlying liver dysfunction with relative prostate volume changes of 86.7 ± 12.0% and 85.0 ± 9.0%, respectively. Conclusion: Our study demonstrated significant PVR with sorafenib treatment in patients regardless of the presence of BPH and underlying liver dysfunction.

Oncolytic viruses (OVs) are novel cancer therapeutics with great promise, but host antiviral immunity represents the hurdle for their efficacy. Immunosuppression by cyclophosphamide (CP) has thus been shown to enhance the oncolytic efficacy of many OVs, but its effects on OVs armed with therapeutic genes remain unknown. We have previously reported on the efficacy of AxE1CAUP, an oncolytic adenovirus (OAd) expressing uracil phosphoribosyltransferase (UPRT), an enzyme that markedly enhanced the toxicity of 5-fluorouracil (5-FU), in immunodeficient, Ad-nonpermissive nude mice. Here we explored the efficacy and safety of intratumoral (i.t.) AxE1CAUP/5-FU therapy and of its combination with CP for syngenic HaP-T1 pancreatic cancers in immunocompetent, Ad-permissive Syrian hamsters. AxE1CAUP infected, replicated, expressed UPRT, and increased the sensitivity to 5-FU in HaP-T1 cells in vitro. I.t. AxE1CAUP/5-FU treatment inhibited the growth of subcutaneous HaP-T1 allografts. The combination with high-dose CP inhibited serum Ad-neutralizing antibody formation, increased intratumoral AxE1CAUP replication and UPRT expression, and resulted in further enhanced therapeutic effects with 5-FU. Neither body weight nor histology of the liver and lung changed during these treatments. A clinically-approved, intermediate-dose CP also enhanced the efficacy of i.t. AxE1CAUP/5-FU treatment in these hamsters, which was not affected by preexisting immunity to the vector. These data demonstrate the excellent antitumor efficacy and safety of an OAd armed with a suicide gene in combination with CP for treating syngenic tumors in immunocompetent, Ad-permissive animals, indicating the efficacy of CP in overcoming the hurdle of antiviral immunity for effective OV-mediated gene therapy.

Purpose To evaluate the feasibility and efficacy of repeated proton beam therapy (PBT) and to analyze the dose–volume relationship. Patients and methods A retrospective analysis was performed in 83 patients who received definitive repeated PBT. Proton beams were delivered with expiratory gating. The numbers of treatment courses were 2, 3, and 4 in 68, 12, and 3 patients, respectively. MIM software was used for dose analysis. Results The planned median total dose was 70.5 GyE for all tumors and the median doses for the 1st, 2nd, 3rd and 4th treatments were 71.0, 70.0, 70.0, and 69.3 GyE, respectively. There was no severe acute toxicity, and no radiation-induced liver dysfunction (RILD) was observed. The median overall survival (OS) period from the first PBT was 61 months (95% CI: 50–71 months), and the 2- and 5-year OS rates were 87.5% (95%CI: 80.2–94.8%) and 49.4% (95%CI: 37.6–61.2%), respectively. The maximal delivered dose to the liver ranged from 66.7 to 248.1 GyE (mean: 124.93 GyE) and the mean liver dose ranged from 5.4 to 66.5 GyE (mean: 24.23 GyE). Conclusion Repeated PBT was well tolerated and safe, even though the liver doses in many patients deviated substantially from well-known critical levels for RILD.

The tumor suppressor gene p53 is the most frequently mutated gene in human cancers. However, its mutation rate is relatively low in gastric cancer compared with other cancers. In this study, we investigated the mechanisms underlying the antitumor effects of nutlin-3, an inhibitor of human homolog of murine double minute 2 (MDM2). MDM2 is a negative regulator of p53. Four gastric cancer cell lines with wild-type p53 (wt p53) and three with mutant-type p53 (mt p53) were analyzed for MDM2 and MDM4 expression by immunoblotting, and for their gene amplification by quantitative real-time PCR. Moreover, the viability of cells exposed to nutlin-3 was examined by WST-8 assay, and the expression of p53 and its downstream genes was analyzed by immunoblotting. Nutlin-3 stabilized p53 and increased the expression of p21(WAF1) and Noxa, and cleaved poly (ADP)-ribose polymerase regardless of the pre-expression levels of MDM2 and MDM4 in gastric cancer cells with wt p53. Flow cytometry revealed that nutlin-3 arrested the cell cycle in G(1) phase and induced apoptosis in the cell lines. These nutlin-3 effects were not observed in the cell lines with mt p53. Nutlin-3 exerted additive or synergistic cytotoxicity in combination with 5-fluorouracil or cisplatin in most cell lines with wt p53. An in vivo antitumor effect of nutlin-3 alone and its additive augmentation by 5-fluorouracil were confirmed in an MDM2 overexpressed xenograft tumor model. Nutlin-3 showed potent antitumor activity against human gastric cancer cells with wt p53 and shows promise as a single agent and in combination with conventional anticancer drugs.

A critical issue in adenovirus (Ad)-based cancer gene therapy is to improve the specificity of gene delivery to cancer cells for better efficacy and safety. We explored methods of retargeting Ad vectors for selective gene therapy of human biliary cancers using the Ad incorporating an IgG Fc-binding motif (Z33) from the Staphylococcus protein A (Ad-FZ33) combined with tumor-specific antibodies. Flow cytometry analysis revealed high-expression levels of epithelial cell adhesion molecule (EpCAM) and epidermal growth factor receptor (EGFR) on human biliary cancer cells. Ad-FZ33 expressing LacZ combined with antibodies against EpCAM or EGFR, followed by β-gal assay, demonstrated highly efficient gene transduction in these biliary cancer cells, compared to the treatment with control antibody or without antibody. Ad-FZ33 expressing uracil phosphoribosyl transferase (UPRT), an enzyme which greatly enhances the toxicity of 5-fluorouracil (FU), combined with antibodies against EpCAM or EGFR, remarkably enhanced the sensitivity of biliary cancer cells to 5-FU. By contrast, the treatment did not affect the 5-FU sensitivity of the cells not expressing EpCAM or EGFR including normal hepatocytes. Finally, treatments with the UPRT-expressing Ad-FZ33 with antibodies against EpCAM or EGFR, followed by 5-FU administration, significantly suppressed the growth of biliary cancer xenografts in nude mice. These results indicate that the gene therapy mediated by the Z33 fiber modified Ad with anti-EpCAM or anti-EGFR antibodies offers a potentially effective therapeutic modality against biliary cancers.

The authors have published a series of studies evaluating the safety and efficacy of proton beam therapy for the treatment of hepatocellular carcinoma in a variety of clinical settings. In the current study, they retrospectively reviewed their entire experience treating hepatocellular carcinoma patients with proton beam therapy at their hospital-based facility at the University of Tsukuba.From November 2001 to December 2007, 333 patients with hepatocellular carcinoma were treated with proton beam therapy at the University of Tsukuba. A total of 318 patients were included in this study. Total dose delivered and fractionation scheme were determined by protocols that varied based on location of tumor. Survival rates and prognostic factors were assessed.Overall actuarial survival rates at 1-year, 3-years, and 5-years were 89.5% (95% confidence interval [95% CI], 85.7-93.1%), 64.7% (95% CI, 56.6-72.9%), and 44.6% (95% CI, 29.7-59.5%), respectively. Child-Pugh liver function (hazards ratio [HR], 2.84; P.01), T stage (HR, 1.94; P.05), performance status (HR, 2.12; P.01), and planning target volume (HR, 2.12; P.05) significantly impacted survival. The 3-year and 5-year survival rates were 69.1% (95% CI, 59.9-78.3%) and 55.9% (95% CI, 41.5-70.3%), respectively, for patients with Child-Pugh A disease and 51.9% (95% CI, 32.3-71.5%) and 44.5% (95% CI, 23.1-65.8%), respectively, for patients with Child-Pugh B disease. The actuarial survival rates of patients with Child-Pugh class A were statistically different between groups of planned target volumeor=125 mL and125 mL (P.05).The authors have shown proton beam therapy to be both safe and effective for the treatment of patients with hepatocellular carcinoma. They strongly recommend the consideration of proton beam therapy in patients for whom other treatment options are risky or contraindicated.

The prognosis of patients with advanced hepatocellular carcinoma (HCC) with portal vein tumor thrombosis (PVTT) is extremely poor, as effective treatment options are limited. The authors performed a retrospective review to evaluate the efficacy of proton-beam therapy (PBT) for patients presenting with PVTT in the setting of HCC.Between February 1991 and September 2005, 35 patients with HCC and tumor thrombi in the main trunk or major branches of the portal vein presented for consideration of PBT. Their tumor sizes ranged from 25 mm to 130 mm (median, 60 mm). A median total dose of 72.6 GyE in 22 fractions was delivered over 31 days to a target volume that encompassed both the primary hepatic lesion and the PVTT.32 patients were progression-free during a median follow-up period of 21 months (range, 2-88 months) and three patients experienced disease progression. Local progression-free survival rates were 46% at 2 years and 20% at 5 years, and the median local progression-free survival was 21 months. Acute toxicityor = grade 3 was observed in three patients, and no patient experienced late toxicityor = grade 3. None of the patients had to discontinue treatment as a result of toxicity.PBT improved local control and significantly prolonged survival in HCC patients with PVTT.

Institutional review board approval and informed consent were obtained. The feasibility of magnetic resonance (MR) imaging with impaired clearance of ferucarbotran to visualize ablated liver parenchyma surrounding a tumor (ablative margin [AM]) was evaluated after radiofrequency (RF) ablation of the liver. Twenty-one patients with hepatocellular carcinomas underwent RF ablation 2-7 hours after ferucarbotran-enhanced MR imaging. On unenhanced T2*-weighted images acquired after 3-5 days, AMs appeared as hypointense rims. The AM status was related to incidence of residual or recurrent tumors. This technique is feasible for visualization of AM and prediction of residual or recurrent tumors after RF ablation of the liver.

Combination therapy with replicative oncolytic viruses is a recent topic in innovative cancer therapy, but few studies have examined the efficacy of oncolytic adenovirus plus replication-deficient adenovirus carrying a suicide gene. We aim to evaluate whether an E1A, E1B double-restricted oncolytic adenovirus, AxdAdB-3, can improve the efficacy for gallbladder cancers (GBCs) of the replication-deficient adenovirus-based herpes simplex virus thymidine kinase (HSVtk)/ganciclovir (GCV) therapy directed by the carcinoembryonic antigen (CEA) promoter. Cytopathic effects of AxdAdB-3 plus AxCEAprTK (an adenovirus expressing HSVtk directed by CEA promoter) or AxCAHSVtk (an adenovirus expressing HSVtk directed by a nonspecific CAG promoter) with GCV administration were examined in several GBC lines and normal cells. Efficacy in vivo was tested in severe combined immunodeficiency disease mice with GBC xenografts. Addition of AxdAdB-3 (1 multiplicity of infection, MOI) significantly enhanced the cytopathic effects of AxCEAprTK (10 MOI)/GCV on GBC cells. The augmented effect was attributable to the replication of the AxCEAprTK and also to the enhanced CEA promoter activity, which was presumably transactivated by E1A. In normal cells, AxdAdB-3 (20 MOI) plus AxCEAprTK (200 MOI)/GCV was not cytopathic, whereas AxdAdB-3 (1 MOI) plus AxCAHSVtk (10 MOI)/GCV was significantly toxic. Low-dose AxdAdB-3 (2 x 10(7) PFU, plaque-forming unit) plus AxCEAprTK (2 x 10(8) PFU)/GCV significantly suppressed the growth of GBC xenografts as compared with either AxdAdB-3 (2 x 10(7) PFU)/GCV or AxCEAprTK (2 x 10(9) PFU)/GCV alone. E1A, E1B double-restricted replicating adenovirus at low dose significantly augmented the efficacy of CEA promoter-directed HSVtk/GCV therapy without obvious toxicity to normal cells, suggesting a potential use of this combination for treating GBC and other CEA-producing malignancies.

Treatment for unresectable intrahepatic cholangiocarcinoma (ICC) has not been established. The aim of the study was to evaluate the outcome of proton beam therapy (PBT) for patients with unresectable ICC.Up to 2010, 20 patients (11 males, 9 females, median age 63 years old) with unresectable ICC (two, seven, seven, and four in stages II, IIIA, IIIC, and IV, respectively) were treated with PBT. The largest dimensions of the tumors ranged from 15 to 140 mm (median: 50 mm). The intrahepatic region and lymph nodes received median total proton doses of 72.6 GyE in 22 fractions and 56.1 GyE in 17 fractions, respectively. Four patients received concurrent chemotherapy (tegafur, gimeracil, and oteracil; TS-1) during PBT. Twelve patients were treated curatively, and eight were treated palliatively because tumors were present outside the irradiation field.In the curative group, nine tumors within the irradiated field were controlled in follow-up of 8.6-62.6 months (median: 20.8 months). Median survival rates in the curative and palliative groups were 27.5 and 9.6 months, respectively, and overall 1- and 3-year survival rates were 82% and 38%, and 50% and 0%, respectively. Eight patients survived for 2 years, and there was no distant metastasis in five of these patients after 2 years. No severe side-effects occurred.The results suggest that long-term survival can be achieved using PBT for patients with unresectable ICC without distant metastasis. Further studies are required to determine the optimal treatment schedule and best combination of PBT and chemotherapy.

In order to enhance the efficacy of conditionally replicating adenoviruses (CRAd) in the treatment of cancers of the biliary tract, we studied the efficacy in vitro and in vivo of AxE1CAUP, a CRAd vector that carries a gene for uracil phosphoribosyltransferase (UPRT), which converts 5-fluorouracil (5-FU) directly to 5-fluorouridine monophosphate and greatly enhances the cytotoxicity of 5-FU. AxE1CAUP replicated and induced an increased UPRT expression in biliary cancer cells more efficiently than AxCAUP, a nonreplicative adenovirus carrying the UPRT gene. Whereas AxCAUP and AxE1AdB, a CRAd without the UPRT gene, modestly increased the sensitivity of BC cells to 5-FU, AxE1CAUP markedly increased the sensitivity, especially when the timing of 5-FU administration was appropriately chosen. AxE1CAUP replicated much less efficiently in normal WI-38 fibroblasts without any change in the sensitivity to 5-FU. In nude mice with s.c. biliary cancer xenografts, i.t. AxE1CAUP/5-FU therapy inhibited tumor growth significantly more strongly than AxCAUP/5-FU or AxE1AdB/5-FU therapy. Furthermore, in mice with peritoneally disseminated biliary cancer, i.p. AxE1CAUP efficiently proliferated in the tumors, decreased the tumor burden, and prolonged the survival of the mice when 5-FU was started 10 or 15 days after the vector inoculation, whereas earlier initiation of 5-FU resulted in early eradication of the vector and no survival benefit. The present study shows that the CRAd expressing UPRT was a more potent sensitizer of biliary cancer to 5-FU, than was a nonreplicative UPRT-encoding vector or a CRAd without UPRT gene, even at a lower dose of the vector, and that timing of 5-FU administration was a key factor to maximize the efficacy. This gene therapy with appropriately timed administration of 5-FU should be useful in overcoming the resistance of biliary cancers to 5-FU.

On thyrotropin-releasing hormone (TRH) metabolism, pyroglutamyl aminopeptidase II (PAP-II), a zinc-dependent ectoenzyme primarily located in the central nervous system, is believed to play a predominant role. Recently we cloned pyroglutamyl aminopeptidase I (PAP-I) which is known for specifically removing a L-pyroglutamate (L-pGlu) residue from the amino terminus of proteins and peptides including TRH. To investigate possible contribution of PAP-I toward TRH metabolism, we conducted biochemical and immunohistochemical characterization using recombinant rat, mouse and human PAP-Is and an antibody raised against rat PAP-I. The Km values toward TRH by the recombinant PAP-Is were about 0.05 mM, being similar value to the reported value of recombinant PAP-II. The L-pGlu-cleaving activities toward TRH in rat brain homogenate were inhibited by a PAP-II specific inhibitor 1,10-phenanthroline, but not inhibited by the antibody against rat PAP-I. Immunohistochemical study in rats revealed heterogeneous distribution of PAP-I in the pituitary, the target tissue of TRH, but the distribution was cytosolic. Taken together, these results suggested that PAP-I might not be dominantly involved in the degradation of TRH in rats. Additionally, we found that PAP-I was localized in the renal proximal tubules. Further investigations are needed for elucidating the function of PAP-I in these restricted sites.

Of pediatric patients with purulent meningitis seen at the institutions listed in the title page of this paper between 1986 and 1994, 93 patients treated with antibiotics and dexamethasone (DXM) were compared with 91 patients treated with antibiotics alone. The patients receiving antibiotics with dexamethasone achieved overall improvement in inflammatory symptoms and signs and cerebrospinal fluid findings and became afebrile significantly earlier than those receiving antibiotics alone. However, some of the patients became febrile again. The secondary fever rate for the DXM group was much higher than that for the antibiotic alone group (p < 0.0001). In most of the rebounded cases, the body temperature rose above 38 degrees C and remained elevated for 2-4 days. Cerebrospinal fluid (CSF) was cultured daily in 54 and 32 patients receiving antibiotics with and without DXM, respectively. Although this study was not a controlled study in a strict sense, these patients compared. In both groups, the CSF became mostly culture-negative within 48 hours. In a few patients receiving DXM, however, it became culture-negative after 72 hours or longer. DXM caused an adverse effect in a patient with meningitis caused by Streptococcus pneumoniae. The adverse effect was mild gastrointestinal bleeding, which recovered spontaneously. From the findings described above, the use of DXM combined with antibiotic therapy was considered to accelerate the relief from fever and improvement of inflammatory symptoms and signs and CSF findings. The body temperature rose again in more than half of the patients receiving DXM, but fell to normal spontaneously without treatment. The elevation doubtlessly could not be distinguished from recurrence of the meningitis itself or complications. It seems to be likely that no treatment but careful observation is required even if the fever recurs as far as the CSF findings showed favorable progress with excelluent general conditions. When DXM is given, it is essential that CSF tests and culture are repeated during the early stages and the progress is monitored carefully.

Interaction between cultured endothelial cells (EC) and pericytes (PC) was studied in vitro to clarify the mechanism of diabetic proliferative retinopathy. Conditioned medium (CM) from retinal PC strongly increased the proliferation and moderately stimulated migration of retinal EC. Moreover, CM from PC caused stimulation of angiogenesis of retinal EC and umbilical cord vein EC in vitro at the same extent as basic fibroblast growth factor (bFGF). PC also stimulated angiogenesis by EC in mixed cultures. The angiogenic, proliferative and migration activities in CM from PC were inhibited by an antibody to bFGF. These data suggest that PC play an important role in angiogenesis through secretion of an FGF-like molecule.

We observed 266 children with purulent meningitis in 27 institutions in Japan during the 14 years from 1981 on dividing these years into 3 periods, 1981-1985, 1986-1990 and 1991-1994, and studied the trend of causative organisms identified in 254 among the 266 patients. Their ages were less than 3 months after birth in 50 children and 3 months or older in 216: there were 141 boys and 125 girls. The causative organisms were H. influenzae in 134 patients and S. pneumoniae in 50, most of them being aged 3 months or older. Next to the above bacteria ranked S. agalactiae in 29 and E. coli in 12, many of the patients were aged less than 3 months. Staphylococcus spp. was found in 7 patients and about 70% of them were aged 3 months or older. L. monocytogenes was found in 4 patients and N. meningitidis in 3 and they were aged 3 months or older in both patient groups. S. pyogenes, Enterococcus spp., Peptostreptococcus spp., P. Mirabilis and Enterobacter spp. were detected each in 1 patient. The causative organism was unknown in 21 patients and there was no double infection. H. influenzae were detected in 18 patients in 1981-1985 period (36.7%), in 56 in 1986-1990 (54.9%) and in 60 in 1991-1994 (63.8%) showing an increasing tendency, but S. pneumoniae exhibited neither an increasing nor decreasing tendency. There was a decreasing tendency with S. agalactiae and E. coli, but the details were not clear because there were few patients aged less than 3 months. Although the period of coexistence of 4 main bacterial species was not made clear in this study. Listeria is considered to develop mainly in the early childhood, and we believe that the conventional way of using a cephem preparation and ampicillin combined for patients under 6 years need not be altered. However, panipenem (phonetic) is likely to be effective for insensible S. pneumoniae for the time being.

We investigated the relationship between the gross motor function and the causes of death and complications in persons with severe motor and intellectual disabilities (SMID).The causes of death, complications and ages of the 777 patients who had been admitted to the wards for persons with SMID in institutions involved in the national hospital organization and died from 1999 to 2008, were reported. Of these patients, 679 patients had data available. The patients were divided into 4 groups; group A (479 cases who could not roll over), group B (31 cases who could roll over but could not sit up), group C (53 cases who could sit up but could not stand up), and group D (22 cases who could stand up but could not walk without support).The frequency of swallowing disturbance in group A was significantly higher than that in the other groups, while the frequency of gastroesophageal reflux was significantly lower in group C than in groups A and B. The percentage of tube feeding in group A was higher than that in the other groups. The differenc between groups A and C was statistically significant. The frequency of tracheotomy in group B was significantly lower than in group A and there were no cases of tracheotomy in groups C and D. Concerning the causes of death, the percentages of respiratory disorders in groups A, B, C, D were 52.4, 32.3, 35.8, 31.8, respectively. The mean age of death in group A was about 10 years younger than in the other groups.The gross motor function predicted the likelihood of respiratory and digestive systems complications and was related to life expectancy.

Lissencephaly is a congenital malformation of the brain characterized by an extensive absence of cerebral gyral formation. Polysomnograms were recorded in 8 cases with lissencephaly (4 of agyria and 4 of pachygyria), and 24-h secretion of growth hormone, prolactin, luteinizing hormone, follicle-stimulating hormone and cortisol was examined in 6 of the 8 cases. The sleep-waking cycle and body temperature (BT) rhythm were studied in all 8 cases. The results were as follows: (i) the sleep-waking circadian rhythm was well preserved in 6 of the 8 cases; (ii) %REM (rapid eye movement) sleep decreased in 4 cases, but the ultradian rhythm of REM sleep was well observed in all cases except one; (iii) the secretion of GH and PRL showed normal or borderline increases with sleep; (iv) although these cases had not reached puberty, LH and FSH increased with sleep in 3 of 5 cases; (v) the circadian rhythm of cortisol secretion was preserved in all cases except one; (vi) BT showed a circadian rhythm after infancy. These findings suggest that the circadian rhythms function normally in lissencephaly, that the secretion of GH and PRL during sleep occurs almost normally, and that the cerebral cortex does not play a significant role in the regulation of these biological rhythms in lissencephaly.

Human hepatitis B virus (HBV) is well known as a cause of membranous nephropathy (MN). While the association of HBV infection with MN is strong, data regarding its association with other glomerular diseases are conflicting. Here, we report a case of focal segmental glomerulosclerosis (FSGS) with HBV infection. In this case, we have found HBV-DNA in urinary podocytes by real-time PCR methods. After the administration of anti-viral therapy, FSGS improved, paralleling the decreased level of HBV-DNA in podocytes. The refractory FSGS induced by HBV could be effectively treated with appropriate anti-viral agents.

Purpose Our previous results for treatment of hepatocellular carcinoma with proton beam therapy (PBT) revealed excellent local control. In this study, we focused on the impact of PBT on normal liver function. Methods and Materials The subjects were 259 patients treated with PBT at the University of Tsukuba between January 2001 and December 2007. We evaluated the Child–Pugh score pretreatment, on the final day of PBT, and 6, 12, and 24 months after treatment with PBT. Patients who had disease progression or who died with tumor progression at each evaluation point were excluded from the analysis to rule out an effect of tumor progression. An increase in the Child–Pugh score of 1 or more was defined as an adverse event. Results Of the 259 patients, 241 had no disease progression on the final day of PBT, and 91 had no progression within 12 months after PBT. In univariate analysis, the percentage volumes of normal liver receiving at least 0, 10, 20, and 30 GyE in PBT (V0, 10, 20, and 30) were significantly associated with an increase of Child–Pugh score at 12 months after PBT. Of the 91 patients evaluated at 12 months, 66 had no increase of Child–Pugh score, 15 had a 1-point increase, and 10 had an increase of ≥2 points. For the Youden index, the optimal cut-offs for V0, V10, V20, and V30 were 30%, 20%, 26%, and 18%, respectively. Conclusion Our findings indicate that liver function after PBT is significantly related to the percentage volume of normal liver that is not irradiated. This suggests that further study of the relationship between liver function and PBT is required.

We investigated the frequency and characteristics of epilepsy in 63 children (39 males and 24 females) with cerebral palsy caused by periventricular leukomalacia, who were born preterm at34 weeks' gestation and followed for more than five years (duration: 5-18 years, mean: 9.6 years). While seven (11%) of the 63 patients had febrile convulsions (FC), 11 (17%) were associated with symptomatic localization-related epilepsy (SLRE) and 8 (13%) with West syndrome (WS). The gestational ages of the WS group were significantly (p0.05) longer than in FC group. The DQ of the SLRE and WS groups were significantly (p0.01) lower than in the N-S group. The frequency of spastic quadriplegia was 19%, 29%, 36%, 50% in the N-S, FC, SLRE, WS groups, respectively. Among the 11 SLER patients, 5 had one seizure type, while 3 had two and 3 had three seizure types. The seizure patterns included complex partial seizures (CPS) in 8, secondarily generalized partial epileptic seizures in 8, and simple partial seizures in 4. One patients in the WS group developed CPS, and another patient developed epilepsy undetermined after infancy. Regarding the main localizing symptoms of SLRE, oculogyric seizures were observed in 7 patients and hemi-facial seizures were observed in 8 patients. In all WS patients, the location of the epileptiform discharges was in the parieto-occipital area, while 8 of 11 patients with SLES had it in the central area.30% of all patients with PVL were associated with epilepsy. WS developed in 13% during early infancy and SLRE developed in 17% after infancy. The most common epileptic seizure in the patients with PVL was complex partial seizure.