Deep learning-based cardiothoracic ratio measurement on chest radiograph: accuracy improvement without self-annotation.

Background: A reproducible and accurate automated approach to measuring cardiothoracic ratio on chest radiographs is warranted. This study aimed to develop a deep learning-based model for estimating the cardiothoracic ratio on chest radiographs without requiring self-annotation and to compare its results with those of manual measurements. Methods: The U-net architecture was designed to segment the right and left lungs and the cardiac shadow, from chest radiographs. The cardiothoracic ratio was then calculated using these labels by a mathematical algorithm. The initial model of deep learning-based cardiothoracic ratio measurement was developed using open-source 247 chest radiographs that had already been annotated. The advanced model was developed using a training dataset of 729 original chest radiographs, the labels of which were generated by the initial model and then screened. The cardiothoracic ratio of the two models was estimated in an independent test set of 120 original cases, and the results were compared to those obtained through manual measurement by four radiologists and the image-reading reports. Results: The means and standard deviations of the cardiothoracic ratio were 52.4% and 9.8% for the initial model, 51.0% and 9.3% for the advanced model, and 49.8% and 9.4% for the total of four manual measurements, respectively. The intraclass correlation coefficients (ICCs) of the cardiothoracic ratio ranged from 0.91 to 0.93 between the advanced model and the manual measurements, whereas those for the initial model and the manual measurements ranged from 0.77 to 0.82. Conclusions: Deep learning-based cardiothoracic ratio estimation on chest radiographs correlated favorably with the results obtained through manual measurements by radiologists. When the model was trained on additional local images generated by the initial model, the correlation with manual measurement improved even more than the initial model alone.

Fat fraction and R2 * values of various liver masses: Initial experience with 6-point Dixon method on a 3T MRI system.

Purpose: To assess the feasibility of the 6-point Dixon method for evaluating liver masses. We also report our initial experience with the quantitative values in various liver masses on a 3T system. Materials and methods: Of 251 consecutive patients for whom 6-point Dixon was employed in abdominal magnetic resonance imaging scans between October 2020 and October 2021, 117 nodules in 117 patients with a mass diameter of more than 1 cm were included in the study. Images for measuring the proton density fat fraction (PDFF) and R2 * values were obtained using the iterative decomposition of water and fat with echo asymmetry and least-squares estimation-quantitative technique for liver imaging. Two radiologists independently measured PDFF (%) and R2 * (Hz). Inter-reader agreement and the differences between readers were examined using intra-class correlation coefficient (ICC) and the Bland-Altman method, respectively. PDFF and R2 * values in differentiating liver masses were examined. Results: The masses included hepatocellular carcinoma (n = 59), cyst (n = 20), metastasis (n = 14), hemangioma (n = 8), and others (n = 16). The ICCs for the region of interest (mm2), PDFF, and R2 * were 0.988 (95 % confidence interval (CI): 0.983, 0.992), 0.964 (95 % CI: 0.949, 0.975), and 0.962 (95 % CI: 0.941, 0.975), respectively. The differences of measurements between the readers showed that 5.1 % (6/117) and 6.0% (7/117) for PDFF and R2 * , respectively, were outside the 95 % CI. Conclusion: Our observation indicates that the 6-point Dixon method is applicable to liver masses.

Radiation dose considerations in digital radiography with an anti-scatter grid: A study using adult and pediatric phantoms.

BACKGROUND: When using an anti-scatter grid, a decrease in receptor dose caused by its X-ray absorption seems to lead to the misperception that radiation dose needs to be increased even in digital radiography (DR). OBJECTIVE: To demonstrate that there is no need to increase radiation dose in DR with a grid, based on a visual evaluation using an adult and a pediatric abdomen phantom (PAD and PPD , respectively). MATERIALS AND METHODS: Phantom images with and without a grid were obtained with exposure parameters determined based on a preliminarily measured signal-to-noise ratio improvement factor (SIF), an index for potential dose reduction when using a grid. In visual evaluation, four radiologists compared phantom images with a grid applied at different dose reduction rates (0% [no reduction], 18%, 36%, and 59% for PAD and 0% and 11% for PPD ) against an image without a grid at the baseline dose (as the reference). They graded the overall image quality of the former relative to that of the latter (reference) on a 3-point scale (3 = better, 2 = almost equal, 1 = worse). RESULTS: The mean scores for dose reduction rates of 0%, 18%, 36%, and 59% were 3.00, 3.00, 2.75, and 1.00, respectively, for PAD ; those for 0% and 11% were 2.13 and 1.63, respectively, for PPD . These results support the validity of our view that no dose increase is necessary when using an anti-scatter grid. Actually, there is even a potential for improvement in image quality with dose reduction rates of ≤36% for PAD . CONCLUSION: It is worth reconsidering the necessity of increasing radiation dose in the DR imaging of the adult and pediatric abdomens with an anti-scatter grid.

Learning vector quantized representation for cancer subtypes identification.

BACKGROUND AND OBJECTIVE: Defining and separating cancer subtypes is essential for facilitating personalized therapy modality and prognosis of patients. The definition of subtypes has been constantly recalibrated as a result of our deepened understanding. During this recalibration, researchers often rely on clustering of cancer data to provide an intuitive visual reference that could reveal the intrinsic characteristics of subtypes. The data being clustered are often omics data such as transcriptomics that have strong correlations to the underlying biological mechanism. However, while existing studies have shown promising results, they suffer from issues associated with omics data: sample scarcity and high dimensionality while they impose unrealistic assumptions to extract useful features from the data while avoiding overfitting to spurious correlations. METHODS: This paper proposes to leverage a recent strong generative model, Vector-Quantized Variational AutoEncoder, to tackle the data issues and extract discrete representations that are crucial to the quality of subsequent clustering by retaining only information relevant to reconstructing the input. RESULTS: Extensive experiments and medical analysis on multiple datasets comprising 10 distinct cancers demonstrate the proposed clustering results can significantly and robustly improve prognosis over prevalent subtyping systems. CONCLUSION: Our proposal does not impose strict assumptions on data distribution; while, its latent features are better representations of the transcriptomic data in different cancer subtypes, capable of yielding superior clustering performance with any mainstream clustering method.

A case of eosinophilic polyangiitis with granulomatosis that evolved to cardiac arrest due to advanced atrioventricular block.

Cardiac manifestations are the major cause of mortality in patients with eosinophilic granulomatosis with polyangiitis (EGPA). Among these manifestations in EGPA patients, in the literature, there are fewer reports describing bradycardia in EGPA patients than those describing tachycardia. A 50-year-old woman with a history of childhood-onset asthma. At age 28, she was diagnosed with eosinophilic gastroenteritis without the diagnosis of EGPA and was started on a systemic steroid and had maintenance daily dose of 2.5 mg after gradually tapered. She had experiencing dizziness and palpitations 2 weeks after discontinuation of the steroid treatment. At emergency visit, electrocardiography revealed an advanced atrioventricular block of 3:1 or less. Forty-eight minutes after the start of electrocardiography, only a P wave was observed and cardiac arrest occurred for 9 s and temporary emergency pacing was performed immediately. She was diagnosed as EGPA presenting leukocyte count, 16,500/µL, 42.8% of which were eosinophils and sinusitis in computed-tomography. She could be survival by treatment of steroid, following the patient to withdraw from an external pacemaker. She received prednisolone of 60 mg, intravenous cyclophosphamide and intravenous immunoglobulin. She had relapsed presenting peripheral eosinophilia, abdominal and numbness in the toes of the left leg pain, but not arrythmia after tapered of prednisolone. Following additional steroid pulse, she had an increase of prednisolone and continued by intravenous cyclophosphamide, intravenous immunoglobulin and started mepolizumab. We presented a severe case of EGPA presenting an advanced atrioventricular block into cardiac arrest.

Peribiliary glands: development, dysfunction, related conditions and imaging findings.

Peribiliary glands are minute structures that are distributed along the intrahepatic large bile ducts, extrahepatic bile duct, and cystic duct. These glands regulate many physiological functions, such as enzyme secretion. Pancreatic exocrine tissues and enzymes are often observed in peribiliary glands; thus, peribiliary glands are involved in enzyme secretion. As such, these glands can be affected by conditions such as IgG4-related sclerosing cholangitis based on commonalities with their pancreatic counterparts. Cystic changes in peribiliary glands can occur de novo, as part of a congenital syndrome, or secondary to insults such as alcoholic cirrhosis. Biliary tree stem/progenitor cells have recently been identified in peribiliary glands. These cells are involved in turnover and regeneration of biliary epithelia as well as in sclerosing reactions in some pathological conditions, such as primary sclerosing cholangitis and hepatolithiasis. Notably, hepatolithiasis is involved in mucin secretion by the peribiliary glands. Additionally, these cells are associated with the manifestation of several neoplasms, including intraductal papillary neoplasm, cystic micropapillary neoplasm, and cholangiocarcinoma. Normal peribiliary glands themselves are particularly small structures that cannot be recognized using any available imaging modalities; however, these glands are closely associated with several diseases, as mentioned above, which have typical imaging features. Therefore, knowledge of the basic pathophysiology of peribiliary glands is helpful for understanding biliary diseases associated with the peribiliary glands.

Early detection of intrahepatic cholangiocarcinoma.

Cholangiocarcinoma (CC) is a malignant tumor which arises from the biliary epithelium and most cases represent adenocarcinoma. CC can be classified into intrahepatic CC (ICC), perihilar CC, and distal CC, based on the site of anatomic origin. The incidence of ICC is increasing in both Western and Eastern countries, while that of extrahepatic cholangiocarcinoma remains fairly stable. ICC infiltrates into adjacent nerves and lymphatic vessels, resulting in progressive disease with a poor prognosis; thus, early detection of ICC is critical for achieving better outcomes and providing better patient care. However, it is difficult for clinicians to detect an ICC, especially in its early stage. Different from hepatocellular carcinoma, the lack of surveillance system for the high-risk group of CC does not allow for a reliable screening examination. In this context, for early detection and diagnosis of ICC, radiologists need to know predisposing conditions that can lead to the development of ICC, such as chronic biliary or hepatic inflammation, primary sclerosing cholangitis, congenital biliary diseases, and other conditions. In this article, we discuss and illustrate the radiologic features of ICC with special attention to early disease stages and of predisposing conditions of ICC.

CT imaging comparison between intraductal papillary neoplasms of the bile duct and papillary cholangiocarcinomas.

OBJECTIVES: To identify imaging features that assist in discriminating intraductal papillary neoplasms of the bile duct (IPNBs) from papillary cholangiocarcinomas (PCCs). METHODS: This study was approved by the institutional review board. Using the recently proposed histological diagnostic criteria for biliary papillary neoplasms, IPNBs and PCCs were selected from 537 biliary neoplasms consecutively resected in a 12.5-year period. Clinical and imaging features were compared between the two groups. RESULTS: The histology review identified 19 IPNBs and 48 PCCs, representing an estimated prevalence of IPNBs among biliary neoplasms of 4%. Approximately one half of IPNBs were incidentally found on imaging conducted for other purposes. In terms of tumor location, 15/19 IPNBs (79%) developed in intrahepatic bile ducts, and 41/48 PCCs (85%) in the distal bile duct. Cystic appearance was highly suggestive for IPNBs (p < 0.001). Using these two parameters, 78% of papillary bile duct neoplasms could be classified into IPNBs or PCCs. Other imaging findings favoring IPNBs included frond-like mural nodule, downstream bile duct dilatation, and the lack of abnormal enhancement in the adjacent bile duct. Interestingly, two patients with non-invasive or microinvasive IPNB had undergone abdominal imaging studies > 3 years before, and a retrospective review of the previous images identified small nodular or cystic lesions, suggesting a less progressive nature of IPNBs than currently thought. CONCLUSIONS: Imaging findings useful for discriminating IPNBs from PCCs appear to be tumor location, shape of tumor, appearance of mural nodules, duct dilatation at unaffected duct, and abnormal enhancement of the adjacent bile duct. KEY POINTS: • Intrahepatic location and cystic dilatation of the affected bile duct are the strong discriminators between IPNBs and PCCs. • The shape of the mural nodule and appearance of the neighboring bile duct are helpful for distinguishing IPNBs and PCCs. • The less aggressive behavior of IPNBs compared with PCCs may facilitate less invasive management in patients with IPNB.

Qualitative and quantitative evaluation for morphological changes of the splenic artery in autoimmune pancreatitis: novel imaging findings for differentiation from pancreatic adenocarcinoma.

PURPOSE: To determine whether morphological changes can occur in the splenic artery (SPA) of autoimmune pancreatitis (AIP) cases, and if present, to compare them with those in pancreatic adenocarcinoma (PAC) to clarify any arterial morphological differences between AIP and PAC. METHODS: A total of 101 AIP cases were included in this study. The presence or absence of morphological change in the SPA was assessed, using arterial phase axial computed tomography images. Subsequently, imaging parameters (imaging pattern, capsule-like rim, other organ involvement, splenic vein [SPV] stenosis, and SPA calcification) were compared between cases with and without morphological changes. Additionally, comparison analyses (visual SPA assessment and % minimal lumen diameter [MLD] stenosis) among normal pancreas, PAC, and AIP groups were performed using early arterial phase (EAP) reconstructed images. RESULTS: In 25 (24.8%) AIP cases, marginal irregularities of the SPA were present. The presence of the capsule-like rim and SPV stenosis were significantly associated with the arterial morphological changes. All cases with morphological changes had a capsule-like rim. Visual assessment using EAP reconstructed images revealed irregularities of the SPA in 9 of 38 AIP cases (23.7%); however, arterial narrowing was not detected in any cases. % MLD stenosis in AIP group was significantly lower than that in PAC group (p < 0.0001). CONCLUSIONS: Although approximately one-quarter of AIP cases potentially demonstrate marginal irregularity in the SPA when it is surrounded by an apparent capsule-like rim, arterial luminal narrowing rarely occurs in contrast to PAC. These arterial findings can help to distinguish AIP from PAC.

Platypnea-orthodeoxia syndrome in the right lateral decubitus position: a case report.

BACKGROUND: Platypnea-orthodeoxia syndrome is a rare syndrome characterized by dyspnea and hypoxia when the patient is sitting or standing. Here we report a case of platypnea-orthodeoxia syndrome caused by a right hemidiaphragmatic elevation with giant liver cyst that triggered a right-to-left shunt through the patent foramen ovale. This case report is the first presentation of a case secondary to hemidiaphragmatic elevation with giant liver cyst. In addition to this, a malposition of the pacemaker lead could be associated with platypnea-orthodeoxia syndrome in this case. CASE PRESENTATION: A 91-year-old Japanese woman presented to our hospital with hypoxia of unknown origin. Severe hypoxia and cyanosis were observed only in the right lateral decubitus position. A chest X-ray and computed tomography scan revealed right hemidiaphragmatic elevation, which was probably compressing the right atrium. A transesophageal echocardiogram showed a compressed right atrium and shunt blood flow in both directions: from the left to the right atrium and vice versa. The shunt flow was exacerbated by postural changes from the left to the right lateral decubitus. A transesophageal echocardiogram also confirmed compression of the right atrium due to giant liver cyst and a malposition of the pacemaker lead abnormally placed in the left atrium through patent foramen ovale. We concluded that the cause of hypoxia was platypnea-orthodeoxia syndrome with right-to-left interatrial shunt through patent foramen ovale. Surgical closure of patent foramen ovale was not performed due to the age of our patient, surgical difficulties, and failure to obtain informed consent. For these reasons she was discharged after receiving medical advice about her posture. CONCLUSIONS: Platypnea-orthodeoxia syndrome is rare and difficult to diagnose. The present case suggests that hypoxia due to postural changes should be considered a differential diagnosis of platypnea-orthodeoxia syndrome.

Generation of a giant coronary artery aneurysm from an intra-plaque cavity with a ruptured fibrous cap: an observation over time through coronary angiography.

A 74-year-old man underwent coronary artery bypass graft surgery. Thirteen years later, he presented with complaints of exertional anterior chest oppression again. Computed tomography coronary angiography revealed the significant stenosis at the mid right coronary artery (RCA). In addition, a giant proximal left anterior descending (LAD) coronary artery aneurysm (CAA) was found. We did not observe this aneurysm on his previous coronary angiogram, performed 12 years previously (i.e., 1 year after his surgery). Diagnostic coronary angiography confirmed the computed tomography findings. We found the significant stenosis at the mid RCA site and a giant proximal LAD coronary artery aneurysm. First, we performed the percutaneous coronary intervention (PCI) at the mid RCA significant stenosis. We implanted the drug eluting stent. After that, we performed PCI to treat the giant proximal LAD coronary artery aneurysm with a covered stent (a 2.8/26-mm polytetrafluoroethylene covered stent), and complete exclusion of the aneurysm was obtained. The etiology of this patient's aneurysm was unclear, but we speculate that the mechanism responsible for the appearance of this aneurysm was the expansion of the intra-plaque cavity with the ruptured fibrous cap. This observation over time through coronary angiography suggests that giant CAAs might be generated asymptomatically under certain conditions. In this case, the possible conditions might have been the chronic total occlusion of the mid-LAD and the significant stenosis just distal to this aneurysm, so increasing flow and pressure against this diseased cavity might have caused this giant CAA to form. In addition, another speculation might have been the local inflammation or macrophage-based degradation after coronary artery bypass graft surgery.

IgG4-related disease: dataset of 235 consecutive patients.

Immunoglobulin G4-related disease (IgG4-RD) is a recently discovered systemic condition, in which various organ manifestations are linked by a similar histological appearance. Our knowledge of this condition is still fragmented, as most studies have examined only a few dozen patients or focused on a particular organ manifestation. This study was conducted to learn the demography and patient characteristics of IgG4-RD using a large cohort. A total of 235 consecutive patients with IgG4-RD, diagnosed in 8 general hospitals in the same medical district, were identified by searching the institutions' radiology database. Inclusion criteria were histology-proven IgG4-RD according to the Pathology Consensus Statement and/or definitive type 1 autoimmune pancreatitis meeting the International Consensus Diagnostic Criteria. Clinical notes and images of selected patients were retrospectively reviewed. All patients were adults (M/F = 4/1). The median age was 67 years (range 35-86). Nine tenths were diagnosed in their 50s to 70s. Among 486 manifestations identified in total, the most common was pancreatitis diagnosed in 142 patients (60%), followed by sialadenitis (34%), tubulointerstitial nephritis (23%), dacryoadenitis (23%), and periaortitis (20%). The majority of patients (95%) had at least 1 of the 5 most common manifestations. Male and female patients differed in their organ manifestations (periaortitis more common in males and sialodacryoadenitis more common in females). Serum IgG4 (normal ≤135 mg/dL) was elevated to >135 mg/dL in 208 patients (88%) and >270 mg/dL in 167 (71%). The IgG4 value was significantly higher in patients with multiorgan involvement than in those with a single manifestation (median 629 mg/dL vs 299 mg/dL, P < 0.01). Of 218 patients, for whom both IgG4 and IgG values were available, the IgG4/IgG ratio was raised to >10% in 194 (89%). Corticosteroids were effective, but the relapse rate was estimated to be 24% in the study period (median 37 months). During the follow-up, 15 malignant diseases were diagnosed in 13 patients (6%). This figure is similar to the incidence (12.9 cancers) expected from the Japanese nationwide study for cancer epidemiology (standardized incidence ratio 1.16). In conclusion, this reliable dataset could improve the characterization of IgG4-RD, particularly its unique demography and the frequency of each organ manifestation.

Immunostaining for polycomb group protein EZH2 and senescent marker p16INK4a may be useful to differentiate cholangiolocellular carcinoma from ductular reaction and bile duct adenoma.

Intrahepatic cholangiocarcinoma arising in chronic advanced liver disease sometimes contains a component of cholangiolocellular carcinoma. Bile duct adenoma, a benign tumor/tumorous lesion and ductular reaction, is also composed of bile ductular cells, and the differential diagnosis is sometimes difficult. We have previously reported that cholangiolocellular carcinoma showed overexpression of a polycomb group protein EZH2, which participates in bypass/escape from cellular senescence during carcinogenesis. In contrast, the ductular reaction showed high expression of senescence-associated p16(INK4a). In this study, we examined whether immunostaining for EZH2 and p16(INK4a) is useful for differential diagnosis among cholangiolocellular carcinoma, bile duct adenoma, and ductular reactions. Subjects included 33 patients with intrahepatic cholangiocarcinoma and combined hepatocellular-cholangiocarcinoma with components of cholangiolocellular carcinoma and 16 patients with bile duct adenoma. The expressions of EZH2 and p16(INK4a) were examined immunohistochemically. The expression of EZH2 was seen in all cases of cholangiolocellular carcinomas, but it was not observed in bile duct adenomas and ductular reactions, which were seen around carcinomas in 80% of cases. The extensive expression of p16(INK4a) was seen only in 4 cases of cholangiolocellular carcinomas (12%). In contrast, the expression of p16(INK4a) was seen in 13 cases (81%) of bile duct adenomas and in all cases of ductular reactions. The borderline between the component of cholangiolocellular carcinoma and the surrounding ductular reaction was clearly highlighted by the reverse expression pattern of EZH2 and p16(INK4a) in 69% of cases. In conclusion, immunostaining for EZH2 and p16(INK4a) may be useful for differential diagnosis among cholangiolocellular carcinomas, bile duct adenomas, and ductular reactions.

Alcohol-related injury to peribiliary glands is a cause of peribiliary cysts: based on analysis of clinical and autopsy cases.

BACKGROUND AND GOAL: Peribiliary cysts, which are known to be associated with various hepatobiliary diseases including alcoholic liver disease, have been reported to originate in the peribiliary glands along the biliary tree. The causal relationship between the peribiliary cysts and alcohol-related hepatic and pancreatic disease were examined in this study. METHODS AND RESULTS: Peribiliary cysts were surveyed in the radiologic reports of out-patients and in-patients at our hospital (between 2007 and 2011), and a total of 31 patients with peribiliary cysts were found; 9 patients were associated with alcoholic liver disease and 2 patients with alcoholic pancreatitis. Among 202 consecutive autopsy cases with a history of heavy drinking (chronic alcoholics) at our Department (between 1990 and 2011), peribiliary cysts were found in 29 cases (14%), and the frequency of these cysts was correlated with the degree of alcohol-related hepatic fibrosis. Interestingly, peribiliary cysts were frequently associated with adenitis of the peribiliary glands (72%), and peribiliary adenitis and cyst formation correlated well with the degree of pancreatic fibrosis. CONCLUSIONS: These results suggest that peribiliary cysts are more likely to occur in chronic alcoholics. The frequent association of peribiliary cysts with the degree of alcohol-related hepatic fibrosis suggests the involvement of the hepatic fibrogenetic process in peribiliary cyst formation. The frequent association of peribiliary adenitis and cyst formation with the degree of pancreatic fibrosis in chronic alcoholics suggests the involvement of alcoholic injuries in the pancreas, resulting in progressive fibrosis, and peribiliary glands, resulting in adenitis and cyst formation.

GNAS and KRAS mutations are common in intraductal papillary neoplasms of the bile duct.

Intraductal papillary neoplasms of the bile duct (IPNB) shows favorable prognosis and is regarded as a biliary counterpart of intraductal papillary mucinous neoplasm (IPMN) of the pancreas. Although activating point mutations of GNAS at codon 201 have been detected in approximately two thirds of IPMNs of the pancreas, there have been few studies on GNAS mutations in IPNBs. This study investigates the status of GNAS and KRAS mutations and their association with clinicopathological factors in IPNBs. We examined the status of GNAS mutation at codon 201 and KRAS mutation at codon 12&13, degree of mucin production and immunohistochemical expressions of MUC mucin core proteins in 29 patients (M/F = 15/14) with IPNB in intrahepatic and perihilar bile ducts (perihilar IPNB) and 6 patients (M/F = 5/1) with IPNB in distal bile ducts (distal IPNB). GNAS mutations and KRAS mutations were detected in 50% and 46.2% of IPNBs, respectively. There was no significant correlation between the status of GNAS mutation and clinicopathological factors in IPNBs, whereas, the status of KRAS mutation was significantly inversely correlated with the degree of MUC2 expression in IPNBs (p<0.05). All IPNBs with GNAS mutation only showed high-mucin production. Degree of mucin production was significantly higher in perihilar IPNBs than distal IPNBs (p<0.05). MUC2 and MUC5AC expression was significantly higher in IPNBs with high-mucin production than those with low-mucin production (p<0.01 and p<0.05, respectively). In conclusions, this study firstly disclosed frequent GNAS mutations in IPNBs, similarly to IPMNs. This may suggest a common histopathogenesis of IPNBs and IPMNs. The status of KRAS mutations was inversely correlated to MUC2 expression and this may suggest heterogeneous properties of IPNBs. IPNBs with high-mucin production are characterized by perihilar location and high expression of MUC2 and MUC5AC, irrespective of the status of GNAS and KRAS mutations.

Overexpression of enhancer of zeste homolog 2 and MUC1 may be related to malignant behaviour in intraductal papillary neoplasm of the bile duct.

AIMS: Intraductal papillary neoplasm of the bile duct (IPNB) usually has a favourable prognosis, but occasionally is associated with invasive carcinoma. Overexpression of the polycomb group protein enhancer of zeste homolog 2 (EZH2) is involved in the progression of malignant tumours. In this study, we examined the significance of EZH2 expression in IPNB and its association with clinicopathological features and the expression of p16(INK4a) , p53 and mucin core proteins. METHODS AND RESULTS: We examined immunohistochemically the expression of EZH2, p16(INK4a) , MUC mucin core proteins and p53 in 15 patients with IPNB without invasion, including the cystic variant [male/female ratio (M/F) = 9/6], and in 19 with IPNB associated with invasive carcinoma (M/F = 13/6). The expression levels of EZH2, p53 and MUC1 were significantly lower (P < 0.01), and of MUC6 were significantly higher (P < 0.05), in IPNB without invasion than in IPNB with invasion. Expression of EZH2 was significantly correlated with expression of MUC1 (P < 0.01) and inversely correlated with expression of MUC6 (P < 0.05). In cholangiocarcinoma cells (HuCTT-1 and TFK-1), knockdown of EZH2 and MUC1 by small interfering RNA decreased invasion and proliferation, whereas knockdown of MUC6 increased invasion. CONCLUSIONS: Overexpression of EZH2 may be associated with malignant behaviour in IPNB in parallel with up-regulated MUC1 expression and down-regulated MUC6 expression.

Immunohistochemical characteristics and malignant progression of hepatic cystic neoplasms in comparison with pancreatic counterparts.

The recent World Health Organization classification for tumors of the digestive system defined grossly and histologically hepatic mucinous cystic neoplasms and intraductal papillary neoplasms of the bile duct separately. In this study, the immunohistochemical features of intraductal papillary neoplasm of the bile duct (19 cases) and hepatic mucinous cystic neoplasm (5 cases) were characterized and compared with those of similar pancreatic lesions, intraductal papillary mucinous neoplasm of the pancreas (12 cases), and pancreatic mucinous cystic neoplasm (6 cases) and with those of other biliary cystic lesions, peribiliary cysts (10 cases). Intraductal papillary neoplasm of the bile duct and intraductal papillary mucinous neoplasm of the pancreas frequently expressed cytokeratin 7; mucin core proteins 1, 2, 5AC, and 6; trypsin; and amylase. Hepatic and pancreatic mucinous cystic neoplasms frequently expressed cytokeratin 7, mucin core proteins 1 and 5AC, estrogen receptor, progesterone receptor, trypsin, and amylase. Estrogen and progesterone receptors were expressed in the subepithelial stromal cells. The groups with intraductal papillary neoplasm of the bile duct and intraductal papillary mucinous neoplasm of the pancreas were different from the groups with hepatic and pancreatic mucinous cystic neoplasm with respect to several phenotypes reflecting gastric and intestinal metaplasia and also the lack of expression of estrogen and progesterone receptors. The Ki-67 and p53 labeling indexes increased significantly with the malignant progression of intraductal papillary neoplasm of the bile duct and intraductal papillary mucinous neoplasm of the pancreas. The p16 labeling index decreased and EZH2 labeling index increased significantly with the malignant progression of intraductal papillary neoplasm of the bile duct and intraductal papillary mucinous neoplasm of the pancreas. In conclusion, intraductal papillary neoplasm of the bile duct and hepatic mucinous cystic neoplasm might be regarded as biliary counterparts of intraductal papillary mucinous neoplasm of the pancreas and pancreatic mucinous cystic neoplasm, respectively, and the mucinous cystic neoplasm and intraductal papillary neoplasm groups differed from each other. Labeling indexes of Ki-67, p53, p16, and EZH2 were comparable in intraductal papillary neoplasm of the bile duct and intraductal papillary mucinous neoplasm of the pancreas along with their malignant progression, suggesting a common carcinogenic process of the tumors.

Bile duct expression of pancreatic and duodenal homeobox 1 in perihilar cholangiocarcinogenesis.

AIMS: Pancreatic and duodenal homeobox 1 (Pdx1) is a transcription factor that is crucial in embryogenic development and differentiation of pancreas, and its overexpression is reportedly involved in the progression of many malignancies, including pancreatic carcinoma. In this study, the role of Pdx1 was examined in cholangiocarcinogenesis. METHODS AND RESULTS: Forty-three cases of human cholangiocarcinoma (CC) and 66 cases of hepatolithiasis or primary sclerosing cholangitis (PSC) with biliary intraepithelial neoplasia (BilIN) lesions and also eight fetal and 20 adult normal livers were examined immunohistochemically. Pdx1 was constantly expressed in the nuclei of fetal bile ducts, but was virtually absent in the large bile ducts of adults. By contrast, Hairy and enhancer of split 1 (Hes1), which represses pancreatic exocrine and endocrine differentiation, was expressed frequently in the adult bile ducts. Pdx1 was expressed in 67% of invasive CCs. In large bile ducts, expression of Pdx1 increased while that of Hes1 decreased during the progression of BilIN lesions to CC. Expression of Pdx1 correlated with proliferative activities in CCs. In an in vitro study, all three CC cell lines expressed Pdx1 mRNA and protein. CONCLUSION: Up-regulation of Pdx1 is a feature of cholangiocarcinogenesis associated with chronic cholangitis. Furthermore, expression of Pdx1 in CC is related to increased proliferative activity in CCs.

Intrahepatic cholangiocarcinomas in cirrhosis are hypervascular in comparison with those in normal livers.

BACKGROUND AND AIMS: Intrahepatic cholangiocarcinomas (ICCs) are usually adenocarcinomas with fibrotic and hypovascular stroma. Intrahepatic cholangiocarcinomas in cirrhosis and precirrhotic liver (ICC-cirrhosis) are increasingly being diagnosed, and can display hypervascular enhancement resembling a hepatocellular carcinoma on dynamic imaging. METHODS: In this study using ICC-cirrhosis (71 cases), ICC with non-specific reactive changes (ICC-reactive) (72 cases) and the cholangiocarcinoma component of combined hepatocellular cholangiocarcinoma (HCC-ICC) (30 cases), we tried to compare the tumour vasculature. RESULTS: It was found that ICC-cirrhosis and the cholangiocarcinoma component of HCC-ICC showed a higher density of arteries and microvessels (1.59 ± 0.58/mm(2) (mean ± SD) and 140 ± 43/mm(2) in ICC-cirrhosis and 1.74 ± 0.67/mm(2) and 131 ± 46/mm(2) in the cholangiocarcinoma component of HCC-ICC) than in ICC-reactive (1.26 ± 0.61/mm(2) and 103 ± 45/mm(2) ). Dynamic computed tomography (CT) and magnetic resonance imaging (MRI) showed that a majority of ICC-cirrhosis displayed strong hypervascular enhancement, whereas one-third of ICC-reactive each showed strong, weak and no or minimal enhancement respectively. The increased vascular density was positively correlated with enhanced arterial phase of dynamic CT and MRI. CONCLUSION: The density of arteries and microvessels of ICC-cirrhosis was higher than that in ICC-reactive and comparable to that in the cholangiocarcinoma component of HCC-ICC, and the higher density of arteries and microvessels in ICC may be responsible for the hypervascular enhancement of ICC-cirrhosis.

Specific immunoadsorption therapy using a tryptophan column in patients with refractory heart failure due to dilated cardiomyopathy.

BACKGROUND: Certain cardiac-specific autoantibodies found in patients with dilated cardiomyopathy (DCM) play a role in mediating myocardial damage and fatal ventricular arrhythmias resulting in sudden cardiac death. Immunoadsorption therapy (IA) is one of the therapeutic tools to remove such autoantibodies. Clinical studies from Germany have shown that nonspecific IA using columns loaded by sheep antihuman IgG or protein A improved hemodynamic data and affected favorably cardiac function and survival in patients with heart failure (HF) due to DCM. The goal of this study is to determine if IA therapy using the high-profile tryptophan column, which has high affinity for IgG3 subclass, affects favorably cardiac function in patients with severe HF who are refractory to conventional therapy. METHODS AND RESULTS: IA therapy was conducted in 16 patients with DCM (age 53 ± 4, male 8, New York Heart Association functional class III/IV, mean ejection fraction 18 ± 2%). Study subjects had autoantibodies directed against either ß1-adrenergic or M2-muscarinic receptors. Plasma brain natriuretic peptide levels were significantly decreased after IA (P = 0.016). Plasma inflammatory cytokines including interleukin-6 and tumor necrosis factor-α did not change after each session of IA. Six-minute walk distance was significantly increased after IA (P = 0.01). Left ventricular ejection fraction increased by 3% 3 months after IA (P = 0.039). CONCLUSIONS: Our initial experience demonstrated safety and short-term efficacy of IA using a new IgG3-specific tryptophan column for patients with advanced HF due to DCM. Long-term follow-up is needed to confirm the effects on cardiac function and morbidity/mortality in such patients.