Diffuse large B-cell lymphoma of the gallbladder with hepatoduodenal invasion exhibiting a necrotic tendency.

We report a case of diffuse large B-cell lymphoma (DLBCL) of the gallbladder with extensive hepatoduodenal invasion, which was challenging to diagnose histologically due to a strong tendency to be necrotic. An 71 year-old man presented with upper abdominal pain and was referred to our hospital. Computed tomography revealed a distended gallbladder with air within the irregular gallbladder wall and an indistinct border with the hepatoduodenum, suggesting invasion. Esophagogastroduodenoscopy detected an ulceration in the duodenal bulb. However, histologic analysis failed to provide a definitive diagnosis due to the presence of necrotic tissue. Furthermore, direct biopsy from the gallbladder mucosa by endoscopic retrograde cholangiography revealed only necrotic tissue and no diagnosis. Contrast ultrasonography for the hepatic invasion revealed enhancement with blood flow, suggesting non-necrotic tissue. Subsequently, an ultrasound-guided core-needle biopsy was conducted to obtain tissue samples from the described lesion. The pathology showed atypical lymphocytes with irregular nuclei. Immunostaining indicated positive expression of CD10, CD20, Bcl-6, and C-Myc, consistent with a diagnosis of DLBCL. In our case, the lymphoma exhibited a strong tendency to be necrotic, making histologic diagnosis difficult. However, selective biopsy from the site of blood flow made the diagnosis possible and proved to be useful.

Narrowing the Patient-Physician Gap Based on Self-Reporting and Monthly Hepatologist Feedback for Patients With Alcohol-Related Liver Disease: Interventional Pilot Study Using a Journaling Smartphone App.

BACKGROUND: Screening and intervention for alcohol use disorders (AUDs) are recommended to improve the prognosis of patients with alcohol-related liver disease (ALD). Most patients' smartphone app diaries record drinking behavior for self-monitoring. A smartphone app can be expected to also be helpful for physicians because it can provide rich patient information to hepatologists, leading to suitable feedback. We conducted this prospective pilot study to assess the use of a smartphone app as a journaling tool and as a self-report-based feedback source for patients with ALD. OBJECTIVE: The aims of this study were assessment of whether journaling (self-report) and self-report-based feedback can help patients maintain abstinence and improve liver function data. METHODS: This pilot study used a newly developed smartphone journaling app for patients, with input data that physicians can review. After patients with ALD were screened for harmful alcohol use, some were invited to use the smartphone journaling app for 8 weeks. Their self-reported alcohol intake, symptoms, and laboratory data were recorded at entry, week 4, and week 8. Biomarkers for alcohol use included gamma glutamyl transferase (GGT), percentage of carbohydrate-deficient transferrin to transferrin (%CDT), and GGT-CDT (GGT-CDT= 0.8 × ln[GGT] + 1.3 × ln[%CDT]). At each visit, their recorded data were reviewed by a hepatologist to evaluate changes in alcohol consumption and laboratory data. The relation between those outcomes and app usage was also investigated. RESULTS: Of 14 patients agreeing to participate, 10 completed an 8-week follow-up, with diary input rates between 44% and 100% of the expected days. Of the 14 patients, 2 withdrew from clinical follow-up, and 2 additional patients never used the smartphone journaling app. Using the physician's view, a treating hepatologist gave feedback via comments to patients at each visit. Mean self-reported alcohol consumption dropped from baseline (100, SD 70 g) to week 4 (13, SD 25 g; P=.002) and remained lower at week 8 (13, SD 23 g; P=.007). During the study, 5 patients reported complete abstinence. No significant changes were found in mean GGT and mean %CDT alone, but the mean GGT-CDT combination dropped significantly from entry (5.2, SD 1.2) to the week 4 visit (4.8, SD 1.1; P=.02) and at week 8 (4.8, SD 1.0; P=.01). During the study period, decreases in mean total bilirubin (3.0, SD 2.4 mg/dL to 2.4, SD 1.9 mg/dL; P=.01) and increases in mean serum albumin (3.0, SD 0.9 g/dL to 3.3, SD 0.8 g/dL; P=.009) were recorded. CONCLUSIONS: These pilot study findings revealed that a short-term intervention with a smartphone journaling app used by both patients and treatment-administering hepatologists was associated with reduced drinking and improved liver function. TRIAL REGISTRATION: UMIN CTR UMIN000045285; http://tinyurl.com/yvvk38tj.

Smad3 Phospho-Isoform Signaling in Nonalcoholic Steatohepatitis.

Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic steatosis with insulin resistance, oxidative stress, lipotoxicity, adipokine secretion by fat cells, endotoxins (lipopolysaccharides) released by gut microbiota, and endoplasmic reticulum stress. Together, these factors promote NAFLD progression from steatosis to nonalcoholic steatohepatitis (NASH), fibrosis, and eventually end-stage liver diseases in a proportion of cases. Hepatic fibrosis and carcinogenesis often progress together, sharing inflammatory pathways. However, NASH can lead to hepatocarcinogenesis with minimal inflammation or fibrosis. In such instances, insulin resistance, oxidative stress, and lipotoxicity can directly lead to liver carcinogenesis through genetic and epigenetic alterations. Transforming growth factor (TGF)-ß signaling is implicated in hepatic fibrogenesis and carcinogenesis. TGF-ß type I receptor (TßRI) and activated-Ras/c-Jun-N-terminal kinase (JNK) differentially phosphorylate the mediator Smad3 to create two phospho-isoforms: C-terminally phosphorylated Smad3 (pSmad3C) and linker-phosphorylated Smad3 (pSmad3L). TßRI/pSmad3C signaling terminates cell proliferation, while constitutive Ras activation and JNK-mediated pSmad3L promote hepatocyte proliferation and carcinogenesis. The pSmad3L signaling pathway also antagonizes cytostatic pSmad3C signaling. This review addresses TGF-ß/Smad signaling in hepatic carcinogenesis complicating NASH. We also discuss Smad phospho-isoforms as biomarkers predicting HCC in NASH patients with or without cirrhosis.

Efficacy of microwave ablation versus radiofrequency ablation for hepatocellular carcinoma: a propensity score analysis.

PURPOSE: To evaluate the efficacy and safety of radiofrequency ablation (RFA) and new-generation microwave ablation (MWA) for the treatment of hepatocellular carcinoma (HCC). METHODS: The propensity score matching method was applied to patients with HCC treated with MWA (93 patients) or RFA (156 patients) at a single institution from January 2014 to April 2020. The local tumor progression (LTP), intrahepatic distant recurrence (IDR), and recurrence-free survival (RFS) of the two matched therapies were analyzed using the Kaplan-Meier method. Cox proportional hazard models were used to identify risk factors for LTP and RFS. The therapeutic effects and complications of the two treatments were also compared. RESULTS: The LTP, IDR, and RFS of MWA and RFA were equivalent (LTP: hazard ratio [HR] = 0.87; 95% confidence interval [95% CI] 0.36- 2.07; P = 0.746, IDR: HR = 1.03; 95% CI 0.61-1.73; P = 0.890, RFS: HR = 1.15; 95% CI 0.69-1.91; P = 0.566). Para-vessel lesions was the only risk factor for LTP, whereas age, previous treatment, Albumin-Bilirubin score, and tumor diameter were risk factors for RFS. On the other hand, the ablation time per nodule (6.79 ± 2.73 and 9.21 ± 4.90 min; P = 0.008) and number of sessions per nodule required to achieve technical success (1.16 ± 0.39 and 1.34 ± 0.57; P = 0.009) were significantly lower in MWA than in RFA. The major complication rate of MWA and RFA was also equivalent. CONCLUSION: MWA and RFA have similar therapeutic effects and safety, although MWA has advantages over RFA regarding efficacy, including shorter ablation time and fewer sessions required.

Phospho-Smad3 signaling is predictive biomarker for hepatocellular carcinoma risk assessment in primary biliary cholangitis patients.

INTRODUCTION: Patients with primary biliary cholangitis (PBC) are at increased risk for development of hepatocellular carcinoma (HCC), particularly in the presence of comorbidities such as excessive alcohol consumption. Although liver fibrosis is an important risk factor for HCC development, earlier predictors of future HCC development in livers with little fibrosis are needed but not well defined. The transforming growth factor (TGF)-ß/Smad signaling pathway participates importantly in hepatic carcinogenesis. Phosphorylated forms (phospho-isoforms) in Smad-related pathways can transmit opposing signals: cytostatic C-terminally-phosphorylated Smad3 (pSmad3C) and carcinogenic linker-phosphorylated Smad3 (pSmad3L) signals. METHODS AND RESULTS: To assess the balance between Smad signals as a biomarker of risk, we immunohistochemically compared Smad domain-specific Smad3 phosphorylation patterns among 52 PBC patients with various stages of fibrosis and 25 non-PBC patients with chronic hepatitis C virus infection. HCC developed in 7 of 11 PBC patients showing high pSmad3L immunoreactivity, but in only 2 of 41 PBC patients with low pSmad3L. In contrast, 9 of 20 PBC patients with minimal Smad3C phosphorylation developed HCC, while HCC did not occur during follow-up in 32 patients who retained hepatic tumor-suppressive pSmad3C. Further, PBC patients whose liver specimens showed high pSmad3L positivity were relatively likely to develop HCC even when little fibrosis was evident. CONCLUSION: In this study, Smad phospho-isoform status showed promise as a biomarker predicting likelihood of HCC occurrence in PBC. Eventually, therapies to shift favorably Smad phospho-isoforms might decrease likelihood of PBC-related HCC.

Short term treatment results of local ablation with water-cooled microwave antenna for liver cancer: Comparison with radiofrequency ablation.

The aim of the present study was to evaluate the efficacy and safety of the new-generation percutaneous microwave ablation (MWA) compared with the radiofrequency ablation (RFA) system for the treatment of hepatocellular carcinoma (HCC). A retrospective study was conducted from January 2014 to February 2019. A total of 44 patients and 52 nodules (mean tumor size, 17.2±4.9 mm) were treated with MWA, and 55 patients and 70 nodules (mean tumor size, 17.7±6.4 mm) were treated with RFA. After 4 days of treatment, the direct effects of ablation were assessed using dynamic CT, and after discharge, a follow-up dynamic CT scan was performed every 3-4 months. Treatment efficacy, complications and local recurrence were recorded. For MWA and RFA, the average number of CT sessions were 1.05±0.23 and 1.28±0.54, respectively, and the mean ablation times were 5.0±2.0 and 8.1±4.8 min. Following MWA and RFA, the ablation ranges that were evaluated with the axial images were 31.9±5.5 and 33.3±9.0 mm, respectively, in the long-axis diameter and 27.6±5.3 and 23.4±6.8 mm, respectively, in the short-axis diameter. The flatness ratios of the ablation regions were 0.13±0.09 and 0.29±0.14 (axial image) and 0.11±0.07 and 0.28±0.14 (coronal image), respectively. The rates of complete tumor necrosis were comparable. The complication rates were 13.6% (MWA) and 14.5% (RFA), which were not significantly different. The cumulative local recurrence rates were not significantly different between the two methods (one-year recurrence rate, MWA: 6.91%, RFA: 5.17%). MWA was therefore indicated to be an effective treatment for HCC in respect to session number, treatment time and spherical ablation.

Smad Phospho-Isoforms for Hepatocellular Carcinoma Risk Assessment in Patients with Nonalcoholic Steatohepatitis.

Nonalcoholic steatohepatitis (NASH)-related hepatocellular carcinoma (HCC) sometimes occurs in mildly fibrotic livers, while HCC incidence in NASH-related cirrhosis is lower than and less predictable than in hepatitis C virus (HCV)-related cirrhosis. Transforming growth factor (TGF)-ß signaling in hepatocytic nuclei is implicated in fibrosis and carcinogenesis. TGF-ßtype I receptor (TßRI) and c-Jun N-terminal kinase (JNK) differentially phosphorylate the mediator Smad3, resulting in 2 distinct phospho-isoforms: C-terminally phosphorylated Smad3 (pSmad3C) and linker-phosphorylated Smad3 (pSmad3L). In mature hepatocytes, oncogenic signaling via the JNK/pSmad3L pathway antagonizes signaling via the tumor-suppressive TßRI/pSmad3C pathway. We immunohistochemically examined domain-specific Smad3 phosphorylation in liver biopsy specimens from 30 NASH patients representing different fibrotic stages and 20 chronically infected hepatitis C patients as controls, correlating Smad3 phosphorylation with clinical course. HCC occurred during follow-up in 11 of 12 NASH patients with abundant pSmad3L and limited pSmad3C but in only 2 of 18 with limited pSmad3L. In contrast, HCC developed in 12 of 15 NASH patients with limited pSmad3C but only 1 of 15 with abundant pSmad3C. Two of fourteen NASH patients with mild fibrosis developed HCC, their hepatocytic nuclei showed abundant pSmad3L and limited pSmad3C. Five of sixteen patients with severe fibrosis did not develop HCC, their hepatocytic nuclei showed limited pSmad3L and abundant pSmad3C. Smad phospho-isoforms may represent important biomarkers predicting HCC in NASH and potential therapeutic targets for preventing NASH-related HCC.

Acute necrotizing pancreatitis as a fatal complication following DC Bead transcatheter arterial chemoembolization for hepatocellular carcinoma: A case report and review of the literature.

Transcatheter arterial chemoembolization (TACE) is one of the most effective palliative measures for patients with inoperable hepatocellular carcinoma (HCC). Acute pancreatitis is a rare but well-known complication following TACE. We herein present the case of a patient with HCC who developed fatal complications (acute necrotizing pancreatitis and upper gastrointestinal ulcers) after TACE with DC Beads. The patient was diagnosed with HCC in segments 4 and 8, measuring ~70 mm in greatest diameter, and he was treated by TACE. Hepatic arteriography revealed replacement of the origin of the right hepatic artery to the superior mesenteric artery, while the left hepatic artery originated from the celiac artery. After selection of the segmental arterial branches feeding the tumor, 2 ml of 100-300-µm-sized DC Beads loaded with 150 mg epirubicin were injected through the microcatheter. The patient complained of abdominal pain after the TACE procedure. Upper gastrointestinal endoscopy revealed longitudinal ulcers from the esophagus to the duodenum, and contrast-enhanced computed tomography revealed swelling of the pancreas and focal areas of low density in the pancreatic body, suggesting necrosis. The patient developed respiratory insufficiency, renal failure and sepsis, and finally succumbed to the complications 54 days after the procedure, despite general management of the acute pancreatitis. An autopsy revealed that the main cause of the patient's death was extensive pancreatic necrosis due to a gastroduodenal artery embolism after TACE with DC Beads. Therefore, it is crucial for treating physicians to be aware of this complication following TACE with DC Beads, particularly in patients with anatomical variations.

Clinico-Pathological Importance of TGF-ß/Phospho-Smad Signaling during Human Hepatic Fibrocarcinogenesis.

Chronic viral hepatitis is a global public health problem, with approximately 570 million persons chronically infected. Hepatitis B and C viruses increase the risk of morbidity and mortality from liver cirrhosis, hepatocellular carcinoma (HCC), and extrahepatic complications that develop. Hepatitis virus infection induces transforming growth factor (TGF)-ß, which influences microenvironments within the infected liver. TGF-ß promotes liver fibrosis by up-regulating extracellular matrix production by hepatic stellate cells. TGF-ß is also up-regulated in patients with HCC, in whom it contributes importantly to bringing about a favorable microenvironment for tumor growth. Thus, TGF-ß is thought to be a major factor regulating liver fibrosis and carcinogenesis. Since TGF-ß carries out regulatory signaling by influencing the phosphorylation of Smads, we have generated several kinds of phospho-specific antibodies to Smad2/3. Using these, we have identified three types of phospohorylated forms: COOH-terminally phosphorylated Smad2/3 (pSmad2C and pSmad3C), linker phosphorylated Smad2/3 (pSmad2L and pSmad3L), and dually phosphorylated Smad3 (pSmad2L/C and pSmad3L/C). TGF-ß-mediated pSmad2/3C signaling terminates cell proliferation; on the other hand, cytokine-induced pSmad3L signaling accelerates cell proliferation and promotes fibrogenesis. This review addresses TGF-ß/Smad signal transduction in chronic liver injuries and carcinogenic processes. We also discuss the reversibility of Smad signaling after antiviral therapy.