Clients' experiences of empathy in genetic counseling for hereditary breast and ovarian cancer: A qualitative study in Japan.

Empathy is a significant element in genetic counseling for building relationships with the clients and addressing their issues. However, there are few reports on the experiences of the clients about their perceived empathy in genetic counseling. Cancer genetic counseling needs have been rapidly evolving with the expansion of clinical comprehensive genomic profiling and genetic diagnosis approaches for hereditary cancers. Therefore, this study aimed to reveal empathy perceptions of the clients during cancer genetic counseling. Semi-structured interviews were conducted, and a grounded theory approach was used for data analysis. A total of 13 participants were recruited from organizations for patients with cancer, among whom 11 were patients with hereditary breast and ovarian cancer (HBOC) and two were relatives of patients with HBOC. Data analysis was organized into five categories related to experiences with empathy: (i) prior context to perceive empathy (ii) understanding and consideration, (iii) bedside manner, and (iv) impacted area of perceived empathy; and (v) no empathy. This study highlights the fact that empathy experiences of the clients differ depending on the situation and state of mind. Taken together, this study provides new insights on how to deliver empathic care.

Bile duct adenoma and small-sized small duct type intrahepatic cholangiocarcinoma show distinct differences in genetic alterations, expression of IMP3 and EZH2 and stromal and inflammatory components.

AIMS: Given that bile duct adenoma was significantly more prevalent in the liver with small duct type intrahepatic cholangiocarcinoma (small duct iCCA), compared to other primary liver carcinomas, we examined the possibility of bile duct adenoma as a precursor of small duct iCCA by analysing genetic alterations and other features in bile duct adenomas. METHODS AND RESULTS: Subjects included 33 bile duct adenomas and 17 small-sized (up to 2 cm in diameter) small duct iCCAs. Genetic alterations were examined by direct sequencing for hot-spot regions and immunohistochemical staining. The expression of p16INK4a , EZH2 and IMP3 and stromal and inflammatory components were also examined. Genetic alterations examined including BRAF were not detected in bile duct adenomas, whereas genetic alterations of p53 (47%), ARID1A (41%), PBRM1 (12%), MTAP (12%), IDH1 (6%), KRAS (6%) and TERT promoter (6%) were detected in 16 small-sized small duct iCCA (94%) (P < 0.01). The expression of IMP3 and EZH2 was not detected in bile duct adenomas, whereas it was detected in most small duct iCCA (94%) (P < 0.01). Immature stroma and neutrophilic infiltration were significantly more prevalent in small duct iCCA, compared to bile duct adenoma (P < 0.01). CONCLUSION: Bile duct adenomas and small-sized small duct iCCAs show distinct differences in genetic alterations, expression of IMP3 and EZH2 and stromal and inflammatory components. There was no evidence suggesting that bile duct adenoma is a precursor of small duct iCCA. Immunohistochemical staining for IMP3, EZH2, p53, ARID1A and MTAP may be useful for differential diagnosis between bile duct adenomas and small duct iCCAs.

Empathy experiences of Japanese certified genetic counselors: A qualitative investigation and proposed framework.

Empathy is an important element of genetic counseling. Most genetic counselors acknowledge the significance of empathically engaging clients. However, few empirical studies have focused on the empathy experience of genetic counselors, especially in non-Western countries. This study aimed to investigate Japanese genetic counselors' perspectives on the concept of empathy in clinical practice. The study conducted semi-structured interviews with Japanese certified genetic counselors who had approximately 10 years of clinical experience. Fourteen participants were interviewed about their thoughts on empathy and their experiences wherein they had deeply understood clients or felt closer to them. The interview data were analyzed using grounded theory. As a result, 17 categories were extracted, of which 13 were integrated into three themes of empathy: the empathic cycle in the relationships between genetic counselors and clients (cycling), the process of forming a deeper understanding of a client's perspectives (feeling), and the process of developing skills to understand clients with empathy (developing). The remaining four categories were grouped into the theme of "challenges of empathy." The categories included in the first three themes were similar to previous findings in Western countries, whereas some categories of challenges of empathy were unique to this study, which was conducted in a non-Western country. This might be attributed to the influence of Japanese culture, in which people emphasize self-regulation and an interdependent-self model. To our knowledge, this study is the first to report on Japanese certified genetic counselors' experiences of empathy. This study concludes with some suggestions for future research, including focusing on ways to overcome challenges of empathy in countries or healthcare systems.

Bile duct adenoma may be a precursor lesion of small duct type intrahepatic cholangiocarcinoma.

BACKGROUND/AIMS: Precursor lesions of small duct type intrahepatic cholangiocarcinoma (small duct iCCA) have not been clarified so far. We hypothesised that precursor lesions may be frequently distributed in the background liver of small duct iCCA. METHODS AND RESULTS: We determined by histology the presence of bile duct adenomas and von Meyenburg complexes as candidate precursor lesions in the background liver of small duct iCCA, with other primary liver carcinomas as control. Subjects included 28 patients with small duct iCCA, 29 with large duct iCCAs, 60 with combined hepatocellular-cholangiocarcinoma (Comb) and 40 with hepatocellular carcinoma (HCC). The prevalence of bile duct adenomas in the background liver was significantly higher in small duct iCCA (35.7%) compared to other primary liver carcinomas (Comb, 4.9%; 10%, HCC) (P < 0.01). The prevalence of bile duct adenomas was significantly associated with the presence of von Meyenburg complexes and ductal plate malformation-like patterns in small duct iCCAs and Combs. Von Meyenburg complexes were detected in 11 small duct iCCA (39.3%), five large duct iCCAs (17.2%), 10 Comb (16.4%) and 13 HCC (33.3%), respectively (P > 0.05). Small duct iCCAs showed altered expression of ARID1A (46.4%), p53 (39.3%), PBRM1 (14.3%), IMP3 (85.7%) and EZH2 (82.1%), whereas these markers were negative in bile duct adenomas. CONCLUSION: Bile duct adenomas may be precursor lesions of small duct iCCAs. Alteration of ARID1A, p53 or PBRM1 may be involved in the carcinogenesis of small duct iCCAs.

Notch-Hes1 signaling activation in Caroli disease and polycystic liver disease.

The Notch signaling pathway plays a key role in the morphogenesis of the biliary tree, but its involvement in cystic biliary diseases, such as Caroli disease (CD) and polycystic liver disease (PLD), has yet to be determined. Immunostaining was performed using liver sections of CD and PLD, and the results were compared with those of congenital hepatic fibrosis (CHF) and von Meyenburg complex (VMC). The expression of Notch receptor 1 (Notch1) was increased in the nuclei of biliary epithelial cells in all cases of CD and PLD, whereas it remained at a low level in CHF and VMC. In addition, Notch2 and Notch3 were preferably expressed in the nuclei of biliary epithelial cells of PLD. Accordingly, the Notch effector Hes1 was highly expressed in biliary epithelial cells of CD and PLD, and the cell proliferative activity was significantly higher in CD and PLD. The expression of the Notch ligand Delta-like 1 was significantly increased in biliary epithelial cells of CD and PLD, which may be causally associated with the nuclear overexpression of Notch1 and Hes1. These results indicate that aberrant activation of the Notch-Hes1 signaling pathway may be responsible for the progression of biliary cystogenesis in CD and PLD.

MET amplification results in heterogeneous responses to osimertinib in EGFR-mutant lung cancer treated with erlotinib.

The third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) osimertinib is approved for untreated, or previously EGFR-TKI-treated T790M-positive EGFR-mutated non-small cell lung carcinoma (NSCLC). We investigated the heterogeneity of responses to osimertinib and its underlying mechanisms. A patient with EGFR-L858R-mutated NSCLC was treated with erlotinib. Following treatment, he developed brain and multiple bone metastases and was eventually diagnosed with NSCLC with EGFR-T790M mutation. The responses of various tumor specimens to osimertinib were heterogeneous. We investigated EGFR-T790M and MET amplification using PCR and FISH in autopsy specimens of the cervical spine, lumbar spine, and brain. We established the KNZ osimertinib-resistant (KNZ_OR) tumor cell line with MET amplification using a cervical spine lesion that was intrinsically resistant to osimertinib. We evaluated the effects of MET knockdown and MET inhibitor on KNZ_OR cell sensitivity to osimertinib in vitro and in vivo. Osimertinib-resistant lesions (cervical spine and brain) showed EGFR-L858R and MET amplification, but not EGFR-T790M, whereas osimertinib-sensitive lesions (lumbar spine) showed EGFR-L858R and -T790, but not MET amplification. Osimertinib decreased the association of amplified MET with L858R-mutated EGFR but increased that with human epidermal growth factor receptor 3 in KNZ_OR cells. MET knockdown or MET inhibitor sensitized KNZ_OR cells to osimertinib in vitro, indicating that MET amplification induced osimertinib resistance. Combination with osimertinib plus crizotinib induced tumor shrinkage in the KNZ_OR xenograft model. Hence, MET amplification might induce heterogeneous responses to osimertinib in EGFR-mutated NSCLC. Further investigations on mutated EGFR and amplified MET might lead to the development of effective therapies.

Increased p16INK4a-expressing senescent bile ductular cells are associated with inadequate response to ursodeoxycholic acid in primary biliary cholangitis.

BACKGROUND & AIMS: Senescent biliary epithelial cells (BECs) may be involved in the pathophysiology of primary biliary cholangitis (PBC) by secreting senescence-associated secretory phenotypes. We examined an association of the extent of cellular senescence in BECs with clinicopathological features including response to ursodeoxycholic acid (UDCA) and a possibility of senolytic therapy in PBC. METHODS: The expression of senescent markers (p21WAF1/Cip1, p16INK4a) and B-cell lymphoma-extra large (Bcl-xL), a key regulator of senescent cell anti-apoptotic pathway, was immunohistochemically examined in livers from patients with PBC (n = 145) and 103 control livers. Senolytic effect of Bcl-xL inhibitors (A-1331852 and Navitoclax) was examined in senescent murine BECs. RESULTS: Senescent BECs were increased in small bile ducts in PBC, compared with control livers (p < 0.01). Senescent BECs were increased in ductular reactions in PBC, stage 3-4, compared with PBC, stage 1-2 and control livers (p < 0.01). The extent of senescent BECs in bile ductules was significantly correlated with stage and hepatitis activity (p < 0.01) and the expression of p16INK4a in bile ductules was significantly correlated to inadequate response to UDCA in PBC (p < 0.01). Double immunofluorescence revealed an increased expression of Bcl-xL in p16INK4a-positive senescent BECs in PBC. Bcl-xL inhibitors selectively induced apoptosis in senescent murine BECs (p < 0.01). CONCLUSION: The extent of senescent BECs in small bile ducts and bile ductules was closely related to stage and activity of PBC and the increased expression of p16 INK4a in bile ductules was correlated with inadequate response to UDCA.

Fulminant myocarditis and pulmonary cavity lesion induced by disseminated mucormycosis in a chronic hemodialysis patient: Report of an autopsied case.

Mucormycosis is a rare fungal infection occurring in the immunocompromised host. It is difficult to diagnose, and its cardiac involvement is extremely rare. Here, we report a 64-year-old Japanese man with a 5-year history of hemodialysis with disseminated mucormycosis causing fulminant myocarditis and pulmonary necrosis under glucocorticoid use. Two months before, he had received an implantable cardioverter defibrillator and started to take amiodarone for recurrent ventricular arrhythmias due to hypertensive cardiomyopathy. He developed amiodarone-induced interstitial pneumonia and then received glucocorticoid therapy. Although the interstitial pneumonia partially improved, a lung cavitary lesion developed in the upper right lobe. Antibiotics had no effect, and serologic tests, blood and sputum cultures and bronchoalveolar lavage fluid were all negative for infectious pathogens. Eventually, he died of fulminant myocarditis. Autopsy revealed disseminated mucormycosis with vascular invasion and fungal thrombi, hemorrhage and infarction in lung (cavity lesion), heart (severe myocarditis), brain, thyroid and subcutaneous tissue around the implantable cardioverter defibrillator. The lung cavitary lesion was the only clinical finding suggestive of mucormycosis before autopsy. When an immunocompromised patient shows a progressive lung cavity lesion, the possibility of mucormycosis should be considered so that a broad-spectrum antifungal agent can be empirically administered in a timely fashion.

Blockade of Hedgehog Signaling Attenuates Biliary Cystogenesis in the Polycystic Kidney (PCK) Rat.

Caroli disease represents a hepatic manifestation of autosomal recessive polycystic kidney disease, and belongs to a class of cholangiociliopathies. The role of Hedgehog signaling, a major pathway regulated by primary cilia, in biliary cystogenesis in Caroli disease remains unknown. Using the polycystic kidney (PCK) rat as an animal model of Caroli disease, this study investigated the involvement of Hedgehog signaling in its pathogenesis. In vitro experiments revealed that PCK cholangiocytes overexpressed Smoothened, Gli1, and Gli1's target molecule cyclin D1. The nuclear expression of Gli1, Gli2, and Gli3 was observed in PCK cholangiocytes by immunocytochemistry. An immunohistochemical analysis using liver sections confirmed the overexpression of Smoothened and cyclin D1, and the nuclear expression of the Gli proteins in the biliary epithelium of PCK rats as well as human Caroli disease. The treatment of PCK cholangiocytes with cyclopamine inhibited cell proliferative activity that was associated with the inhibition of nuclear translocation of Gli1 and Gli2, and reduced cyclin D1 expression. The in vivo administration of cyclopamine to PCK rats decreased abnormally elevated serum liver enzymes, and significantly attenuated bile duct dilation as well as kidney cyst formation. These results suggest that cholangiocyte hyperproliferation is causally associated with the aberrant activation of Hedgehog signaling, and the inhibition of the signaling has potential as a therapeutic strategy for biliary cystogenesis in Caroli disease.

[A Case of Peritoneal Mesothelioma Diagnosed by Ileus].

The present case involved a man aged about 70 years. He visited our hospital with the main complaint of abdominal pain. We diagnosed him with intestinal obstruction, and we decided to perform surgery. White knot sections were spread inside the abdominal cavity, and the small intestine appeared as a single block. This block was resected and examined for peritoneal mesothelioma. Peritoneal mesothelioma is thought to have incubation period of 20-25 years after exposure to asbestos, and the number of affected patients will increase in the future. In some cases, peritoneal mesothelioma occurs only in the peritoneum; therefore, diagnosis often becomes difficult. Once intestinal obstruction occurs, administering chemotherapy is difficult. Therefore, early diagnosis is thought to be very important.

An impaired biliary bicarbonate umbrella may be involved in dysregulated autophagy in primary biliary cholangitis.

Dysregulated autophagy may be a central player in trehe pathogenesis of primary biliary cholangitis (PBC) by inducing autoimmune processes via abnormal expression of mitochondrial antigens such as pyruvate dehydrogenase complex, E2 component (PDC-E2) and also by inducing cellular senescence in biliary epithelial cells (BECs) in bile duct lesions in PBC. We examined the association of an impaired "biliary bicarbonate umbrella" due to dysfunction of anion exchanger 2 (AE2) with dysregulated autophagy and cellular senescence in PBC. The expression of AE2 was examined in cultured BECs treated with bile acids such as glycochenodeoxycholic acid (GCDC) and tauro-ursodeoxycholic acid (TUDCA), various cytokines (IL-4, IL-13, IFNγ, TNFα, TGFß), and serum deprivation. The effect of AE2 knockdown using siRNA on autophagy, cell surface expression of PDC-E2, and cellular senescence was also examined. The expression of AE2 and its association with autophagy-related markers and senescent markers p16INK4a and p21WAF1/Cip1 were immunohistochemically determined in livers taken from the patients with PBC (n = 50) and 69 control diseased and normal livers. The expression of AE2 was significantly induced in the cultured BECs shortly treated with GCDC and other stresses, whereas it was significantly decreased in senescent BECs induced by GCDC and other stresses (p < 0.05). Dysregulated autophagy, cell surface expression of PDC-E2, and cellular senescence were significantly increased by knockdown of AE2 (p < 0.05). The expression of AE2 was significantly decreased in cholangitis in PBC, compared to control livers (p < 0.05). The decreased expression of AE2 was correlated with dysregulated autophagy, abnormal expression of PDC-E2, and cellular senescence in bile duct lesions in PBC. In conclusion, an impaired biliary bicarbonate umbrella may be involved in the pathogenesis of PBC by inducing dysregulated autophagy.

Increased expression of senescence-associated cell cycle regulators in the progression of biliary atresia: an immunohistochemical study.

AIMS: Cellular senescence plays a role in tumour suppression and in the pathogenesis of various non-neoplastic diseases, including primary biliary cholangitis and other adult cholangiopathies. Less is known about the role of cellular senescence in cholangiopathies in children. With that in mind, we examined the expression of senescence-associated cell cycle regulators in biliary atresia, the most common form of paediatric obliterative cholangiopathy. METHODS AND RESULTS: The expression of senescence-associated cell cycle regulators (p16Ink4a and p21WAF1/Cip1 ) and a ductular reaction related marker (neural cell adhesion molecule: NCAM) was examined in bile ducts and bile ductules in liver samples taken from the patients with biliary atresia [n = 80; including 23 samples at the time of the Kasai procedure (KP) and 63 obtained from the explanted liver (LT) (six cases with samples at both surgical stages of disease)] and from appropriate controls (n = 17). The degree of ductular reaction and cholestasis was significantly more extensive in LT than KP (P < 0.01). The expression of p16INK4a and NCAM was significantly more extensive in bile ducts and bile ductules in ductular reaction in both KP and LT compared to controls and in LT compared to KP (P < 0.05). The expression of p21WAF1/Cip1 was significantly more extensive in bile ducts and bile ductules in KP compared to both LT and controls (P < 0.01). CONCLUSIONS: Cellular senescence may play a role in the progression of bile duct loss in biliary atresia in a manner similar to that of adult cholangiopathies.

Mutational landscape of combined hepatocellular carcinoma and cholangiocarcinoma, and its clinicopathological significance.

AIMS: Combined hepatocellular carcinoma and cholangiocarcinoma (cHC-CC), which generally has a poor prognosis, comprises hepatocellular carcinoma (HCC), cholangiocarcinoma (CC), and diverse components with intermediate features between HCC and CC. Histological subtypes with stem cell (SC) features (the SC subtype) have different clinicopathological significance in cHC-CC. The mutational status may reflect the clinicopathological subgroup of cHC-CC together with the histological subtype. METHODS AND RESULTS: We examined the mutational statuses of KRAS, IDH1 or IDH2 (IDH1/2), ARID1A, the TERT promoter, and TP53, and their relationships with clinicopathological features in 53 patients with cHC-CC. Background liver diseases were hepatitis B (n = 9), hepatitis C (n = 22), alcoholic liver disease (n = 5), non-alcoholic fatty liver disease (NAFLD) (n = 8), and unknown (n = 9). Mutations in KRAS, IDH1/2, ARID1A, the TERT promoter and TP53 were detected in four (7.5%), six (11.8%) seven (13.2%), 16 (31.3%), and 24 patients (45.3%), respectively. KRAS mutations correlated with higher histological diversity scores and a higher M-factor (P < 0.05). ARID1A mutations correlated with alcoholic liver disease, smaller tumour size, a lower grade of coexistent HCC, and α-fetoprotein (AFP) positivity, and were associated with cholangiolocellular carcinoma subtype predominance (P < 0.05). TERT promoter mutations correlated with hepatitis B, an intermediate subtype-predominant histology, higher clinical stage, and a higher N-factor (P < 0.05), and were associated with gender (female-predominant) and previous therapy. TP53 mutations correlated with AFP positivity (P < 0.05). CONCLUSIONS: The results of the mutational analysis revealed that cHC-CC has diverse types of mutations, and also that mutations in the TERT promoter and ARID1A may reflect aetiological impact, different histological subtypes, histogenesis, and tumour aggressiveness. These results suggest the potential efficacy of molecular-based subclassification of cHC-CC.

Bile Acids and Deregulated Cholangiocyte Autophagy in Primary Biliary Cholangitis.

BACKGROUND: Primary biliary cholangitis (PBC) is characterized by a high prevalence of serum anti-mitochondrial antibodies against the E2 subunit of the pyruvate dehydrogenase complex and bile duct lesions called chronic non-suppurative destructive cholangitis (CNSDC) in small bile ducts, eventually followed by extensive bile duct loss and biliary cirrhosis. Macroautophagy (a major type of autophagy) is a process of cellular self-digestion that plays a critical role in energy homeostasis and in the cytoprotection to various stresses. Deregulated autophagy is thought to be associated with various human diseases. Key Messages: Accumulating evidences suggest that deregulated autophagy may be a central player in the pathogenesis of PBC. Damaged cholangiocytes involved in CNSDC show vesicular expression of autophagy marker LC3 and accumulation of p62/sequestosome-1, suggesting deregulated autophagy. Deregulated autophagy may be involved in the autoimmune process via the abnormal expression of mitochondrial antigens and also in cholangiocyte senescence in bile duct lesions in PBC. In vitro study showed that hydrophobic bile acids, such as glycochenodeoxycholic acid (GCDC), as well as serum deprivation and oxidative stress, cause autophagy, deregulated autophagy and abnormal expression of mitochondrial antigens followed by cellular senescence in cholangiocytes. Although exact mechanisms of deregulated autophagy remain to be clarified, endoplasmic reticulum (ER) stress may be a plausible cause of deregulated autophagy induced by GCDC in cholangiocytes. Impaired 'biliary bicarbonate umbrella' may further exacerbate the toxicity of GCDC to cholangiocytes. Interestingly, pretreatment with ursodeoxycholic acid (UDCA) and tauro-UDCA, which is a chemical chaperone enhancing the adaptive capacity of the ER, significantly suppressed ER stress, deregulated autophagy and cellular senescence induced by GCDC and other stresses in cholangiocytes. CONCLUSIONS: GCDC may play a role in the occurrence of deregulated autophagy and cellular senescence at least partly through the induction of ER stress in PBC. Deregulated autophagy and cellular senescence can be a promising therapeutic target in PBC.

The PD-1/PD-L1 axis may be aberrantly activated in occupational cholangiocarcinoma.

An outbreak of cholangiocarcinoma in a printing company was reported in Japan, and these cases were regarded as an occupational disease (occupational cholangiocarcinoma). This study examined the expression status of programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1) in occupational cholangiocarcinoma. Immunostaining of PD-1, PD-L1, CD3, CD8, and CD163 was performed using tissue sections of occupational cholangiocarcinoma (n = 10), and the results were compared with those of control cases consisting of intrahepatic (n = 23) and extrahepatic (n = 45) cholangiocarcinoma. Carcinoma cells expressed PD-L1 in all cases of occupational cholangiocarcinoma, whereas the detection of PD-L1 expression in cholangiocarcinoma cells was limited to a low number of cases (less than 10%) in the control subjects. In cases of occupational cholangiocarcinoma, occasional PD-L1 expression was also noted in precancerous/preinvasive lesions such as biliary intraepithelial neoplasia and intraductal papillary neoplasm of the bile duct. Additionally, tumor-associated macrophages and tumor-infiltrating T cells expressed PD-L1 and PD-1, respectively. The number of PD-L1-positive mononuclear cells, PD-1-positive lymphocytes, and CD8-positive lymphocytes infiltrating within the tumor was significantly higher in occupational cholangiocarcinoma compared with that in control cases. These results indicate that immune escape via the PD-1/PD-L1 axis may be occurring in occupational cholangiocarcinoma.

Benign Hepatocellular Nodules: Hepatobiliary Phase of Gadoxetic Acid-enhanced MR Imaging Based on Molecular Background.

Gadoxetic acid is a contrast agent for magnetic resonance (MR) imaging with hepatocyte-specific properties and is becoming increasingly important in detection and characterization of hepatocellular carcinoma and benign hepatocellular nodules, including focal nodular hyperplasia (FNH), nodular regenerative hyperplasia (NRH), hepatocellular adenoma (HCA), and dysplastic nodule. In these hepatocellular nodules, a positive correlation between the grade of membranous uptake transporter organic anion-transporting polypeptide (OATP) 1B3 expression and signal intensity in the hepatobiliary (HB) phase has been verified. In addition, it has been clarified that OATP1B3 expression is regulated by activation of ß-catenin and/or hepatocyte nuclear factor 4α. On the other hand, recent studies have also revealed some of the background molecular mechanisms of benign hepatocellular nodules. FNH commonly shows iso- or hyperintensity in the HB phase with equal or stronger OATP1B3 expression, with map-like distribution of glutamine synthetase (a target of Wnt/ß-catenin signaling) and OATP1B3 expression. NRH shows doughnut-like enhancement with hypointensity in the central portion in the HB phase with OATP1B3 expression. The majority of HCAs show hypointensity in the HB phase, but ß-catenin-activated HCA exclusively demonstrates iso- or hyperintensity with increased expression of nuclear ß-catenin, glutamine synthetase, and OATP1B3. Dysplastic nodule commonly shows iso- or hyperintensity in the HB phase with similar to increased OATP1B3 expression, but one-third of high-grade dysplastic nodules can be demonstrated as a hypointense nodule with decreased OATP1B3 expression. Knowledge of these background molecular mechanisms of gadoxetic acid-enhanced MR imaging is important not only for precise imaging diagnosis but also understanding of the pathogenesis of benign hepatocellular nodules. ©RSNA, 2016.

Autophagy and senescence in fibrosing cholangiopathies.

Fibrosing cholangiopathy such as primary sclerosing cholangitis (PSC) and biliary atresia (BA) is characterized by biliary epithelial injuries and concentric fibrous obliteration of the biliary tree together with inflammatory cell infiltration. In these diseases, inappropriate innate immunity is reported to contribute more to bile duct pathology as compared with various aspects of "classical" autoimmune diseases. Primary biliary cirrhosis (PBC) is characterized by chronic cholangitis with bile duct loss and classical autoimmune features. Cellular senescence of cholangiocytes and a senescence-associated secretory phenotype lead to the production of proinflammatory cytokines and chemokines that may modify the milieu of the bile duct and then trigger fibroinflammatory responses in PSC and PBC. Furthermore, deregulated autophagy might be involved in cholangiocyte senescence and possibly in the autoimmune process in PBC, and the deregulated innate immunity against enteric microbes or their products that is associated with cholangiocyte senescence might result in the fibrosing cholangitis that develops in PBC and PSC. In BA, innate immunity against double-stranded RNA viruses might be involved in cholangiocyte apoptosis and also in the development of the epithelial-mesenchymal transition of cholangiocytes that results in fibrous obliteration of bile ducts. These recent advances in the understanding of immune-mediated biliary diseases represent a paradigm shift: the cholangiocyte is no longer viewed merely as a passive victim of injury; it is now also considered to function as a potential effector in bile duct pathology.

Clinicopathological characteristics of serum amyloid A-positive hepatocellular neoplasms/nodules arising in alcoholic cirrhosis.

AIMS: To characterize serum amyloid A (SAA)-positive hepatocellular neoplasms/nodules arising in alcoholic cirrhosis, which are detected as hypervascular hepatocellular nodules resembling hepatocellular carcinoma on imaging. METHODS AND RESULTS: Fifty-three hepatocellular nodules were examined with immunostaining for SAA, glutamine synthetase and glypican-3 in 23 patients (four women and 19 men) with alcoholic cirrhosis. Sixteen nodules were examined with magnetic resonance imaging with gadolinium ethoxybenzyl diethylenetriaminepentaacetic acid enhancement (EOB-MRI). Somatic mutations in IL6ST, GNAS and STAT3 were examined in 19 nodules. Thirty-six nodules in 18 patients were diagnosed as SAA-positive hepatocellular neoplasms/nodules, and the remaining 17 nodules in eight patients were SAA-negative focal nodular hyperplasia (FNH)-like nodules. SAA-positive hepatocellular neoplasms/nodules showed significantly more extensive sinusoidal dilatation, inflammatory reaction, abnormally thick arteries and cellular atypia than FNH-like nodules (P < 0.05). Eight SAA-positive hepatocellular neoplasms/nodules (67%) showed slight hypointensity in the hepatobiliary phase on EOB-MRI, whereas all four FNH-like nodules showed iso-intensity (P < 0.05). STAT3 mutations were detected in two of 17 SAA-positive hepatocellular neoplasms/nodules. CONCLUSIONS: This study showed that approximately two-thirds of hypervascular hepatocellular nodules arising in alcoholic cirrhosis were SAA-positive hepatocellular neoplasms/nodules, which show different findings on the EOB-MRI. STAT3 mutations were detected in 11.8% of SAA-positive hepatocellular neoplasms/nodules, supporting a neoplastic nature.

Clinicopathological significance of 'subtypes with stem-cell feature' in combined hepatocellular-cholangiocarcinoma.

BACKGROUNDS & AIMS: Combined hepatocellular-cholangiocarcinoma (cHC-CC), a malignant liver tumour with poor prognosis, is composed of hepatocellular carcinoma (HCC), cholangiocarcinoma (CC) and diverse components with intermediate features between HCC and CC, which correspond to hepatic progenitor cells. According to the WHO classification 2010, we surveyed the prevalence and clinicopathological significance of each subtype with stem-cell features [SC subtype; typical subtype (TS), intermediate cell subtype (INT) and cholangiolocellular type (CLC)] in cHC-CC and HCC. METHODS: Sixty-two patients with cHC-CC (19 women and 43 men) and 26 patients with HCC (all men) were examined. The prevalence of each component was histologically assessed with assistance of mucin and immunohistochemical stainings. RESULTS: SC subtypes were observed in all cHC-CCs in various amount and combination. The prevalence of each SC subtype in cHC-CC was as follows: TS, 10 (16.1%); INT, 53 (83.9%) and CLC, 44 (71.0%). The proportion of INT was significantly correlated with gender (female-dominant) (P < 0.05), tumour size (P < 0.05), histological grading of HCC (P < 0.01) and inversely correlated with the degree of stromal fibrosis (P < 0.05). The proportion of CLC was significantly correlated with the degree of fibrosis (P < 0.01) and inflammation (P < 0.01), and inversely correlated with tumour size (P < 0.01) and histological grading of HCC (P < 0.05). The proportion of TS was significantly inversely correlated with the degree of inflammation (P < 0.01). Histological diversity score was significantly correlated with vascular invasion and the positivity for α-foetoprotein. CONCLUSION: The proportion of each SC subtype was significantly associated with certain clinicopathological factors, suggesting different properties of each SC subtypes.

Serum Amyloid A-Positive Hepatocellular Neoplasm: A New Type of Tumor Arising in Patients with Advanced Alcoholic Disease.

This chapter reviews a new type of hepatocellular neoplasm, serum amyloid A-positive hepatocellular neoplasm (SAA-HN), which arises in patients with advanced alcoholic liver disease such as cirrhosis. SAA-HNs share histological and immunohistochemical features with inflammatory hepatocellular adenoma, for example, a strong immunoreactivity for SAA. Clinicopathological features and issues regarding SAA-HN are reviewed with emphasis regarding its potential to develop into hepatocellular carcinoma.