[A case of autopsy-confirmed duodenal perforation due to calcium polystyrene sulfonate].

A 77-year-old male patient was referred to our hospital because of jaundice. He was diagnosed with alcoholic liver cirrhosis and was admitted to our hospital because of liver failure. After admission, we observed conservative liver disease, but the liver damage did not improve and gradually worsened. Renal function deteriorated during liver failure. Hyperkalemia presented due to renal dysfunction. Hence, calcium polystyrene sulfonate (CPS) was initiated. He died because of liver failure although hyperkalemia improved. An autopsy revealed ulcer perforation with CPS crystals in the duodenum. A basic substance considered a crystal of CPS was found by hematoxylin and eosin staining from the ulcer adjacent to the perforation and the exudate attached to the peritoneum. Furthermore, a large amount of CPS crystals were found in the ascites. A final diagnosis of gastrointestinal perforation peritonitis due to CPS was made. Gastrointestinal perforation due to CPS is presumed as a direct mucosal injury due to the drug, most of which is the sigmoid colon of elderly patients. Upper gastrointestinal tract perforation is extremely rare. We experienced a case of autopsy in which duodenal perforation due to CPS was pathologically confirmed. CPS is a widely used drug for renal disorders, but it has a risk of gastrointestinal injury. Therefore, a potential gastrointestinal mucosal injury should be considered when using CPS.

Sorafenib Rechallenge and Sorafenib after Lenvatinib Failure in a Patient with Hepatocellular Carcinoma.

A 70-year-old man was diagnosed with multiple lung metastases from hepatocellular carcinoma, and lenvatinib was initiated. Three months later, the response was progressive disease. Sorafenib therapy as a second-line drug was started. Three months later, the lung metastases had shrunk. After the sorafenib failure, the patient received regorafenib treatment for six months until failure. After the regorafenib failure, sorafenib rechallenge therapy as a fourth-line treatment was initiated. The sorafenib rechallenge, which continued for two months, induced a partial response. Sorafenib after lenvatinib failure and sorafenib rechallenge may be a good option, but further prospective studies are needed.

A fat containing combined neuroendocrine carcinoma and hepatocellular carcinoma in the liver: A case report.

A 79-year-old man was admitted to our hospital because of increased hepatobiliary enzyme levels. Dynamic computed tomography and magnetic resonance imaging showed a liver tumor measuring 60mm containing fat foci at the cranial aspect of the tumor. We diagnosed the patient with hypovascular hepatocellular carcinoma (HCC) and fat deposition, and performed a caudate lobe resection. Pathology examination revealed two intermingled components: moderately differentiated HCC with fat deposition and neuroendocrine carcinoma (NEC). Primary combined NEC and HCC is extremely rare. To our knowledge, this is the first report of combined NEC and HCC including a fat component. HCC is the most common primary hepatic malignancy with fat. HCC might include fat, even if HCC coexists with another type of cancer. The imaging characteristics of and HCC with another type of cancer vary depending on the amount of each component. We should not simply diagnose such tumors as HCC, but think about the possibilities of HCC with another type of cancer, because there is a fat component.

[Successful biliary drainage by percutaneous transhepatic puncture common bile duct and rendezvous technique for a case of recurrent biliary pancreatitis with a Roux-en-Y reconstruction and without extension of the bile duct].

A 92-year-old woman was hospitalized with upper abdominal pain. She had a history of acute biliary pancreatitis and chronic heart failure and had undergone gastrectomy with Roux-en-Y reconstruction. She was admitted with recurrent pancreatitis and an exacerbation of heart failure. Biliary drainage could not successfully be achieved endoscopically or with percutaneous transhepatic biliary drainage and EUS-guided biliary drainage because of the Roux-en-Y reconstruction and non-dilation of bile duct. We successfully accomplished biliary drainage in one session with percutaneous transhepatic puncture of the common bile duct with ultrasound guidance and the rendezvous technique. We report this case because it is rare.

[A case of relapsed hemosuccus pancreaticus successfully treated with interventional radiology].

A 67-year-old male with chronic pancreatitis presented with upper abdominal pain and melena. Abdominal dynamic computed tomography revealed a splenic artery aneurysm in the main pancreatic duct. Esophagogastroduodenoscopy showed active bleeding from Vater's papilla. The patient was diagnosed with hemosuccus pancreaticus (HP) due to rupture of the aneurysm and treated with interventional radiology (IVR). The patient's poor lung function did not allow for a radical operation and a follow-up examination was recommended. The HP relapsed 7 months later and was successfully retreated with IVR. Although IVR is associated with a high recurrence rate, it is less invasive and therefore effective for treating relapsing HP in patients with a poor general condition.

Contrast-enhanced ultrasonography evaluation of hepatocellular carcinoma with peritumoral fat-spared area: a case report.

Peritumoral fat-spared area (PTFSA), a focal spared area surrounding hepatic tumors, is a specific finding of liver tumors in fatty livers. PTFSA mimics a liver tumor, making it difficult to recognize the tumor boundary. We report a case of a 56-year-old man with fatty liver who was diagnosed with a liver tumor. Ultrasonography (US) revealed a nearly homogeneous hyperechoic liver tumor measuring 40 mm in the left lobe. A thick hypoechoic area was observed around the tumor that spread more widely than an ordinary halo. Histological examination revealed that the hypoechoic area comprised a thin fibrous capsule and normal liver parenchyma without fat, which is PTFSA. Contrast-enhanced US (CEUS) indicated corona enhancement only at the inner part of the PTFSA. The inner part showed the same pattern as that of an ordinary halo and was a part of hepatocellular carcinoma, whereas the outer part showed the same pattern as that of the other liver parenchyma. CEUS was an effective modality for distinguishing the difference. Thus, CEUS was useful in defining the tumor boundary. Before initiating treatment, tumors should be evaluated using various modalities to detect their accurate boundary. CEUS may be a useful modality for detecting the boundary and making a diagnosis.

Hepatitis C Treatment with Sofosbuvir and Ledipasvir Accompanied by Immediate Improvement in Hemoglobin A1c.

BACKGROUND/AIMS: Direct-acting antiviral agents (DAAs) have increased the sustained viral response rate with minimal adverse effects and short treatment duration. In addition, recent data suggest the possibility that hepatitis C virus (HCV) clearance results in rapid improvement in metabolic pathways. The aim of the present study was to evaluate whether the DAA treatment without ribavirin lowers hemoglobin A1c (HbA1c) at 12 weeks after therapy completion. METHODS: We performed an observational study to assess the effect of sofosbuvir and ledipasvir (SOF/LED) treatment on glycemic control. We compared HbA1c levels before and after treatment with SOF/LED, considering that anemia is not a side effect of these drugs. RESULTS: In the 36 patients with HCV eradication, HbA1c levels decreased significantly after treatment (pre-treatment 5.85% vs. post-treatment 5.65%, p < 0.01). CONCLUSION: This pilot study shows the possibility that HCV eradication by SOF/LED was accompanied by an improvement of glucose metabolism in the population with or without diabetes, and suggests further investigation.

A case of resected hepatocellular carcinoma after drug-eluting bead transarterial chemoembolization.

We report a case of resected hepatocellular carcinomas (HCCs) after drug-eluting bead transarterial chemoembolization (DEB-TACE). A 67-year-old man with alcoholic liver disease was diagnosed with HCCs. Serological markers for hepatitis B and C viruses were negative. Among tumor markers, alpha-fetoprotein was 2.7ng/mL, and protein induced by vitamin K absence II was 868mAU/mL. Two HCCs were detected using dynamic computed tomography: one was 9cm in diameter in S8 and the other was 2cm in diameter in S4. We performed DEB-TACE using HepaSphere(®) and epirubicin. DEB-TACE was repeated three times in three months. Severe postembolization syndrome was not seen with any treatment. Four weeks after the last DEB-TACE, we performed surgical resection. Histopathological study revealed dense distribution of numerous bead particles in necrotic tumor tissue. Otherwise, in non-cancerous tissue, some beads were in portal areas, without necrotic change. Granulomas from foreign body reaction with giant cells were present around the beads. There were no necrotic changes in the smaller HCC, the intrahepatic metastatic nodules, or the microscopic invasion to the portal vein. In conclusion, DEB-TACE would be a useful treatment for huge HCCs; however, patients should be monitored for early recurrence from residual tumor tissue. This study will be helpful to perform DEB-TACE in the future.

Hepatic inflammation facilitates transcription-associated mutagenesis via AID activity and enhances liver tumorigenesis.

Chronic inflammation triggers the aberrant expression of a DNA mutator enzyme, activation-induced cytidine deaminase (AID), and contributes to tumorigenesis through the accumulation of genetic aberrations. To gain further insight into the inflammation-mediated genotoxic events required for carcinogenesis, we examined the role of chronic inflammation in the emergence of genetic aberrations in the liver with constitutive AID expression. Treatment with thioacetamide (TAA) at low-dose concentrations caused minimal hepatic inflammation in both wild-type (WT) and AID transgenic (Tg) mice. None of the WT mice with low-dose TAA administration or AID Tg mice without hepatic inflammation developed cancers in their liver tissues over the 6 month study period. In contrast, all the AID Tg mice with TAA treatment developed multiple macroscopic hepatocellular carcinomas during the same observation period. Whole exome sequencing and additional deep-sequencing analyses revealed the enhanced accumulation of somatic mutations in various genes, including dual specificity phosphatase 6 (Dusp6), early growth response 1 (Egr1) and inhibitor of DNA binding 2 (Id2), which are putative tumor suppressors, in AID-expressing liver with TAA-mediated hepatic inflammation. Microarray and quantitative reverse transcription-polymerase chain reaction analyses showed the transcriptional upregulation of various genes including Dusp6, Egr1 and Id2 under hepatic inflammatory conditions. Together, these findings suggest that inflammation-mediated transcriptional upregulation of target genes, including putative tumor suppressor genes, enhances the opportunity for inflamed cells to acquire somatic mutations and contributes to the acceleration of tumorigenesis in the inflamed liver tissues.

Accumulation of somatic mutations in TP53 in gastric epithelium with Helicobacter pylori infection.

BACKGROUND & AIMS: Helicobacter pylori infection is a risk factor for gastric cancer. To explore the genetic basis of gastric cancer that develops in inflamed gastric mucosa, we investigated genetic aberrations that latently accumulate in nontumorous gastric epithelium with H pylori infection. METHODS: We performed whole-exome sequencing of gastric tumors, noncancerous tissues with gastritis, and peripheral lymphocytes from 5 patients. We performed additional deep-sequencing analyses of selected tumor-related genes using 34 gastritis mucosal samples from patients with or without gastric cancer. We also performed deep sequencing analyses of gastric mucosal tissues from mice that express transgenic human TP53 and constitutively express activation-induced cytidine deaminase (AICDA or AID) (human TP53 knock-in/AID-transgenic mice). RESULTS: Whole-exome sequencing revealed that somatic mutations accumulated in various genes in inflamed gastric tissues. Additional deep-sequencing analyses of tissues from regions of gastritis confirmed nonsynonymous low-abundance mutations in TP53 in 15 cases (44.1%) and ARID1A in 5 cases (14.7%). The mutations that accumulated in gastric mucosal tissues with H pylori-induced gastritis, as well as gastric tumors, were predominantly C:G>T:A transitions in GpCpX motifs-a marker of cytidine deamination induced by AID. Constitutive expression of AID in the gastric mucosa of mice led to mutations in the human TP53, at amino acid coding positions identical to those detected in human gastric cancers. CONCLUSIONS: Studies of gastric tumors and tissues from humans and mice indicate that somatic mutations accumulate in various genes in gastric mucosal tissues with H pylori infection. Increased cytidine deaminase activity in these tissues appears to promote the accumulation of these mutations and might promote gastric carcinogenesis in patients with H pylori infection.

Leptin receptor somatic mutations are frequent in HCV-infected cirrhotic liver and associated with hepatocellular carcinoma.

BACKGROUND & AIMS: Hepatocellular carcinoma develops in patients with chronic hepatitis or cirrhosis via a stepwise accumulation of various genetic alterations. To explore the genetic basis of development of hepatocellular carcinoma in hepatitis C virus (HCV)-associated chronic liver disease, we evaluated genetic variants that accumulate in nontumor cirrhotic liver. METHODS: We determined the whole exome sequences of 7 tumors and background cirrhotic liver tissues from 4 patients with HCV infection. We then performed additional sequencing of selected exomes of mutated genes, identified by whole exome sequencing, and of representative tumor-related genes on samples from 22 cirrhotic livers with HCV infection. We performed in vitro and in vivo functional studies for one of the mutated genes. RESULTS: Whole exome sequencing showed that somatic mutations accumulated in various genes in HCV-infected cirrhotic liver tissues. Among the identified genes, the leptin receptor gene (LEPR) was one of the most frequently mutated in tumor and nontumor cirrhotic liver tissue. Selected exome sequencing analyses detected LEPR mutations in 12 of 22 (54.5%) nontumorous cirrhotic livers. In vitro, 4 of 7 (57.1%) LEPR mutations found in cirrhotic livers reduced phosphorylation of STAT3 to inactivate LEPR-mediated signaling. Moreover, 40% of Lepr-deficient (C57BL/KsJ-db/db) mice developed liver tumors after administration of thioacetamide compared with none of the control mice. CONCLUSIONS: Based on analysis of liver tissue samples from patients, somatic mutations accumulate in LEPR in cirrhotic liver with chronic HCV infection. These mutations could disrupt LEPR signaling and increase susceptibility to hepatocarcinogenesis.

Visualization of blood drainage area from hypervascular hepatocellular carcinoma on ultrasonographic images during hepatic arteriogram: Comparison with depiction of drainage area on contrast-enhanced ultrasound.

AIM: Corona enhancement is the visualized drainage area from a hypervascular tumor observed on single-level dynamic computed tomography during hepatic arteriography (CTHA) and is thought to be a high-risk area for micrometastases. However, because it cannot be visualized with ordinary ultrasonography (US), we aimed to visualize corona enhancement on US by means of arterial injection of the contrast material and to measure its thickness. METHOD: Forty-one hypervascular hepatocellular carcinoma (HCC) cases were prospectively investigated. US during hepatic arteriography (USHA) was executed by means of selective injection of the contrast material perfluorobutane (Sonazoid) from the hepatic artery. Ordinary contrast-enhanced US with venous administration of contrast material and single-level dynamic CTHA were also performed. RESULTS: Corona enhancement was observed in 36 cases (88%) on USHA and in 25 cases (61%) on single-level dynamic CTHA. The thickness of corona enhancement of 36 cases visualized with USHA ranged 3.1-18.4 mm and the mean thickness ± standard deviation was 6.0 ± 3.0 mm. Thickness of corona enhancement was less than 10.0 mm in 34 cases (94%). CONCLUSION: Corona enhancement could be visualized even on US images, and the average thickness of them was 6 mm.

[A case of primary liver carcinoma of intermediate (hepatocyte-cholangiocyte) phenotype: comparison of hemodynamics and histopathology].

A 58-year-old man was followed up for HBV-associated chronic hepatitis. A low echoic hepatic nodule 1.6cm in diameter developed in segment 8 of the liver. The tumor was hypervascular and showed enhancement on CV during hepatic arteriography (CTHA) and a defect on CT during arterial portography (CTAP). Strong enhancement, which lasted for 30 seconds, was observed at the margin of the tumor on single-level dynamic CTHA. The resected tumor was whitish, had no capsule, and consisted mainly of intermediate immature cells together with HCC-like and CCC-like tumor cells. These findings led to the diagnosis of primary liver carcinoma of intermediate (hepatocyte-cholangiocyte) phenotype. Cytokeratin (CK) 7, CK8, CK19, EMA and vimentin were positive and HP-1 and c-kit tests were negative on immunohistochemical staining. Staining with CD34+alphaSMA showed more muscular arterial vessels and sinusoid-like vessels in the peripheral zone of the tumor than in the central zone. Six months after the resection of the tumor, swollen abdominal lymph nodes were observed on US and CT, which aspiration needle biopsy showed to be metastasis of a hepatic tumor.

[Seven cases of gemcitabine-induced lung injury during treatment for pancreatic or biliary tract cancers].

Gemcitabine is an anti-cancer drug known to be safe and effective for pancreatic or biliary tract cancers, but lung injury is also known to be a rare side effect that sometimes becomes severe. Here we report seven cases of lung injury during gemcitabine treatment. Drug-induced lung injury was suspected in all cases. The male: female ratio was 5:2, and the average patient age was 71. Four had pancreatic cancers and three had biliary tract cancers. Gemcitabine had been administered an average 5.9 times at a dose of 1,141 mg. Patients showed a diffuse or patchy shadow mainly in the lower lung on computed tomography examination. Grades of adverse events were greater than 3 in all cases. Three patients died of the lung injury. Five cases had pulmonary emphysema, 2 had metastatic lung tumor as underlying pulmonary lesions, and these were assumed to have been important risk factors for drug-induced interstitial lung injury during gemcitabine treatment.

[A case of focal nodular hyperplasia presenting corona enhancement on single-level dynamic CT during hepatic arteriography].

A hepatic nodule was detected in segment 5/6 on abdominal US study in a 28 year-old male. The nodule was 7cm in diameter and the early phase of contrasted US, CT and MRI images showed spoke-wheel like vessels radiating from the center. No defect images were observed on postvascular phase contrasted US and SPIO MRI, which indicated the presence of Kupffer cells in the nodule. The nodule was diagnosed as a focal nodular hyperplasia (FNH) based on histological findings. The late phase of single level dynamic CT during hepatic arteriography (CTHA) showed corona enhancement of the nodule, which is considered to be characteristic of hypervascular metastatic liver tumors, hyperplastic nodules and HCCs. In our case, the drainage flow from the nodule may have been visualized as corona enhancement via the pathway from the sinusoid in the nodular periphery to the one in the adjacent and contiguous parenchyma.

[Case of moderately differentiated hepatocellular carcinoma with gastric metastasis].

A solitary liver nodule about 1cm in diameter was detected in a 68-year-old male HBV carrier during therapy for advanced lung cancer. A multiple IIc-like depressed lesion originating in the stomach soon became elevated as the liver lesion progressed. HE staining produced hepatoma-like histological findings for the tumors of the lung, liver and stomach, while immunohistochemical staining showed them to be positive for PIVKA-II and weakly positive for HP-1. Autopsy led to a diagnosis of a moderately differentiated hepatocellular carcinoma producing bile juice with metastasis to the lung and stomach. It is not clear why advanced metastasis in the lung occurred while the hepatocellular carcinoma in the liver was still small, but one possible explanation lies in the localization of the hepatic cancer: the tumor was located near a branch of the hepatic vein and vascular invasion may have caused early pulmonary metastasis via the hepatic venous flow.