Severe functional tricuspid regurgitation due to wild-type transthyretin amyloid cardiomyopathy without left ventricular hypertrophy: a case report.

Background: Transthyretin amyloid cardiomyopathy (ATTR-CM) is usually characterized by left ventricular (LV) hypertrophy or LV systolic dysfunction. However, right atrial (RA) amyloidosis without LV hypertrophy, leading to severe functional tricuspid regurgitation (FTR), is extremely rare. Case summary: We present 75-year-old female with exertional dyspnoea and pre-syncope. Transthoracic echocardiography showed a normal LV function and no LV hypertrophy. A sick sinus syndrome and severe FTR due to right ventricular (RV) and RA dilatation were observed. A leadless cardiac pacemaker implantation was performed for sick sinus syndrome and the symptoms improved, but she complained of leg oedema and fatigue on effort again. A repeated transthoracic echocardiogram showed no notable changes in LV function, but progression of RV and RA dilatation was observed, with worsening FTR. Despite treatment of loop diuretics with 30 mg daily of azosemide, symptoms did not improve, and the patient underwent tricuspid valve annuloplasty. Pathological findings from right atrium led to a diagnosis of ATTR-CM, and deoxyribonucleic acid sequence analysis did not indicate any typical mutation, which supported a diagnosis of wild type of ATTR-CM (ATTRwt-CM). She has been asymptomatic after the surgical operation. She has also been treated with 80 mg daily of tafamidis meglumine to prevent further accumulation of transthyretin in the myocardium and potentially improve long-term outcomes. Discussion: Isolated atrial amyloidosis, especially occurring predominantly in the right atrium and caused by ATTRwt-CM without LV hypertrophy, is extremely rare. However, differential diagnosis should be considered for patients with unexplained dilatation of the right-sided heart or bradyarrhythmia.

A case of pulmonary leiomyosarcoma achieving long-term survival after multiple metastasectomies.

A 58-year-old man who underwent lower lobectomy of the right lung for primary pulmonary leiomyosarcoma (PPL) 4 years ago presented with epigastric pain and was diagnosed with small bowel intussusception caused by an intestinal mass. Partial resection of the small intestine was performed, and pathological examination revealed metastatic leiomyosarcoma. Masses in the left adrenal gland, subcutaneous tissue of the left upper arm, right pleura, jejunum, right trapezius muscle, and right adrenal gland were subsequently detected in the following 4 years. Resection was performed for each tumor, which was histologically confirmed as metastatic leiomyosarcoma. However, 1 month after the last surgery, multiple systemic metastases were found, thus, he is currently undergoing chemotherapy. The patient has been alive for 8 years and 4 months after the first operation for PPL. PPL is an extremely rare disease with no established treatment strategy for recurrences. Aggressive metastasectomy may be beneficial in selected cases.

Alveolar Epithelial Denudation Is a Major Factor in the Pathogenesis of Pleuroparenchymal Fibroelastosis.

The pathogenesis of pleuroparenchymal fibroelastosis (PPFE), a rare interstitial lung disease, remains unclear. Based on previous reports and our experience, we hypothesized that alveolar epithelial denudation (AED) was involved in the pathogenesis of PPFE. This multicenter retrospective study investigated the percentage of AED and the features of the denudated areas in 26 PPFE cases, 30 idiopathic pulmonary fibrosis (IPF) cases, and 29 controls. PPFE patients had lower forced vital capacities and higher residual volume/total lung capacities in pulmonary function tests compared to IPF and control patients. Histopathologically, subpleural fibroelastosis was observed in PPFE, and AED was observed in 12.01% of cases in the subpleural or interlobular septa regardless of fibroelastosis. The percentage of AED in the PPFE group was significantly higher than that in the IPF group (6.84%; p = 0.03) and the normal group (1.19%; p < 0.001). In the IPF group, the percentage of AED and the presence of PPFE-like lesions in the upper lobes were examined radiologically, but no correlation was found. We showed that AED frequently occurred in PPFE. AED was less frequent in IPF, which, in combination with imaging data, suggests that PPFE may have a different pathogenesis from IPF.

Prognostic Value of the Right Ventricular Ejection Fraction, Assessed by Fully Automated Three-Dimensional Echocardiography: A Direct Comparison of Analyses Using Right Ventricular-Focused Views versus Apical Four-Chamber Views.

BACKGROUND: Right ventricular (RV) three-dimensional echocardiographic (3DE) data sets are acquired from either the RV-focused view (RVFV) or the apical four-chamber view (4CV). The prognostic value of 3DE RV ejection fraction (RVEF) was investigated using fully automated RV quantification software, and how measurement values with 3DE data sets from the RVFV compare with those from the 4CV was determined. METHODS: One hundred seventy-four patients who had undergone both cardiac magnetic resonance (CMR) and 3DE imaging were retrospectively selected. RV 3DE data sets were acquired from both the RVFV and the 4CV and were analyzed separately using fully automated RV quantification software. Primary end points were cardiac events, including cardiac death, heart failure requiring hospitalization, nonfatal myocardial infarction, and ventricular tachyarrhythmia. RESULTS: The feasibility of RVEF measurements on 3DE imaging from the RVFV and 4CV was 92% and 92%, respectively. There was good correlation (r = 0.83) and small bias (0.3%) between RVEF from the RVFV and that from the 4CV. Similar results were obtained when only data from patients whose echocardiograms had poor image quality in one or both views were analyzed (r = 0.83, bias = 1.7%, n = 78). Although fully automated analysis in both the RVFV and 4CV significantly underestimated RV volumes compared with CMR, neither measurement differed significantly for RVEF compared with CMR. During a median follow-up period of 12.5 months, 21 patients experienced primary end points. RVEF assessed by CMR and 3DE imaging was significantly associated with cardiac events. RVEF using fully automated analysis had a significant association with cardiac events, even in patients with poor image quality (RVFV: hazard ratio, 0.90 [P = .009, n = 44]; 4CV: hazard ratio, 0.90 [P = .009, n = 68]). CONCLUSIONS: RV 3DE data sets from the RVFV and 4CV yielded similar RVEF values using fully automated software. RVEFs from both approaches had significant association with outcomes. Thus, both provide accurate information regarding RV function and risk for adverse outcomes.

Potential mechanism of left ventricular spherical remodeling: association of mitral valve complex-myocardium longitudinal tissue remodeling mismatch.

Since mitral valve (MV) complex (MVC) longitudinally bridges left ventricular (LV) base end and its middle, insufficient MVC longitudinal tissue length (TL) elongation relative to whole LV myocardial longitudinal TL elongation could limit LV-base-longitudinal-TL elongation, leading to predominant LV-base-transverse-TL elongation, constituting LV spherical remodeling. In 30 patients with dilated cardiomyopathy (DCM), 30 with aortic regurgitation (AR), and 30 controls, LV sphericity, LV-apex- or base-transverse- and longitudinal-TL, MVC-longitudinal-TL, and whole-LV-longitudinal-TL were measured by three-dimensional (3D) echocardiography. Ratio of each measure versus mean normal value (i.e., LV-apex-transverse-TL ratio) was considered to express the directional and regional tissue elongation. [LV-base-longitudinal-TL ratio/global-LV-TL ratio] and [MVC-longitudinal-TL ratio/whole-LV-longitudinal-TL ratio] were obtained as the degree of LV-base-longitudinal-TL or MVC-longitudinal-TL elongation relative to the whole LV elongation. LV-apex-transverse-, LV-apex-longitudinal-, and LV-base-transverse-TL ratios were significantly increased (1.27 to 1.42, P < 0.01) in both DCM and AR, while the LV-base-longitudinal-TL ratio was not increased in DCM [1.04 ± 0.19, not significant (ns)] and only modestly increased in AR (1.12 ± 0.21, P < 0.01). Whole-LV-longitudinal-TL ratio was significantly increased in both DCM and AR (1.22 ± 0.18 and 1.20 ± 0.16, P < 0.01), while MVC-longitudinal-TL ratio was not or only modestly increased in both groups (1.07 ± 0.15, ns, and 1.12 ± 0.17, P = 0.02, respectively). Multivariable analysis revealed that LV sphericity was independently related to a reduced [LV-base-longitudinal-TL ratio/global-LV-TL ratio] (standard ß = -0.42, P < 0.01), which was further related to a reduced [MVC-longitudinal-TL ratio/whole-LV-longitudinal-TL ratio] (standard ß = 0.72, P < 0.01). These are consistent with the hypothesis that relatively less MVC-longitudinal-TL elongation in the process of primary LV myocardial tissue elongation may limit LV-base-longitudinal-TL elongation, contributing to LV spherical remodeling.NEW & NOTEWORTHY Left ventricular (LV) spherical remodeling is associated with poor prognosis and less-effective cardiac performance, which commonly develops in dilated cardiomyopathy. However, its mechanism remains unclear. We hypothesized and subsequently clarified that less mitral valve complex (MVC) tissue longitudinal elongation relative to whole LV myocardial tissue longitudinal elongation is related to disproportionately less LV base longitudinal versus transverse myocardial tissue elongation, constituting spherical remodeling. This study suggests modification of MVC tissue elongation could be potential therapeutic targets.

Importance of Nonlongitudinal Motion Components in Right Ventricular Function: Three-Dimensional Echocardiographic Study in Healthy Volunteers.

BACKGROUND: Global right ventricular (RV) function is determined by the interplay of different motion components related to the myofiber architecture, and the relative importance of these components is still not thoroughly characterized. The aims of this study were to quantify the relative contributions of longitudinal, radial, and anteroposterior motion components to global RV function and to examine their determining factors in a large cohort of healthy volunteers using three-dimensional echocardiography. METHODS: Three hundred healthy adults with a balanced age range and an equal sex distribution were investigated at two centers. A three-dimensional mesh model of the right ventricle was generated, and its motion was decomposed along the three anatomically relevant axes. Multiplicative relative contributions were measured by dividing the ejection fraction (EF) values generated by shortening in the longitudinal, radial, and anteroposterior directions by global RV EF (longitudinal EF index [LEFi], radial EF index [REFi], and anteroposterior EF index, respectively). The circumferential contribution was defined as shortening in the radial and anteroposterior directions, omitting only longitudinal shortening. RESULTS: Circumferential EF index was markedly higher compared with LEFi (79 ± 7% vs 47 ± 9%, P < .001). LEFi (47 ± 9%) and anteroposterior EF index (49 ± 7%) were found to be similar in the pooled population, whereas REFi (44 ± 10%) was lower (P < .001). In younger individuals (20-39 years of age), the relative contribution of longitudinal shortening was significantly higher compared with the radial component; however, in the older age groups, LEFi and REFi were comparable. Age, body surface area, heart rate, and RV end-diastolic volume were independent predictors of LEFi and REFi, but all with opposite effects on the two motion directions. CONCLUSIONS: In contrast to the traditional viewpoint, the contributions of the radial and anteroposterior motion directions may be of comparable significance with that of longitudinal shortening in determining global RV function. Standard parameters referring only to longitudinal shortening of the right ventricle may be inadequate to characterize RV function thoroughly.

Prediction of cardiac events using fully automated GLS and BNP titers in patients with known or suspected heart failure.

BACKGROUND: Although global longitudinal strain (GLS) measurements provide useful predictive information, measurement variability is still a major concern. We sought to determine whether fully automated GLS measurements could predict future cardiac events in patients with known or suspected heart failure (HF). METHODS: GLS was measured using fully automated 2D speckle tracking analysis software (AutoStrain, TomTec) in 3,150 subjects who had undergone clinically indicated brain natriuretic peptide (BNP) assays and echocardiographic examinations. Among 1,514 patients in the derivation cohort, optimal cut-off values of BNP and GLS for cardiac death (CD) and major adverse cardiovascular events (MACEs) were determined using survival classification and regression tree (CART) analysis. The remaining 1,636 patients, comprising the validation cohort, were stratified into subgroups according to predefined cut-off values, and survival curves were compared. RESULTS: Survival CART analysis selected GLS with cut-off values of 6.2% and 14.0% for predicting CD. GLS of 6.9% and 13.9% and BNP of 83.2 pg/mL and 206.3 pg/mL were selected for predicting MACEs. For simplicity, we defined GLS of 7% and 14% and BNP of 100 pg/mL and 200 pg/mL as cut-off values. These cut-off values stratify high-risk patients in the validation cohort with known or suspected HF for both CD and MACEs. CONCLUSIONS: In addition to BNP, fully automated GLS measurements provide prognostic information for patients with known or suspected HF, and this approach facilitates clinical work flow.

Estimation of B-type Natriuretic Peptide Values from N-Terminal proBNP Levels.

Both brain natriuretic peptide (BNP) and N-terminal proBNP (NT-proBNP) are established biomarkers that are necessary in the diagnosis and management of heart failure (HF). However, it is difficult to infer BNP concentration from NT-proBNP concentration for a clinician who is familiar with BNP. We investigated whether estimated BNP concentration from NT-proBNP has an equivalent prognostic strength compared with the actual BNP concentration in the prediction of future outcomes. We created a formula for estimating BNP concentration using multivariate analysis in a derivation cohort with known or suspected HF (n = 374). We determined whether the estimated BNP level had a similar prognostic power compared with the actual BNP and NT-proBNP levels in a validation cohort (n = 375). There was a strong correlation between log-transformed BNP and log-transformed NT-proBNP (r = 0.90) in the derivation cohort. We created two types of equation from the derivation cohort. During a median of 1 year of follow up, 49 major adverse cardiac events developed in the validation cohort. Cox proportional analysis revealed that the actual and estimated BNP levels represented equivalent and significant predictors of the future cardiovascular outcome. The estimated BNP levels calculated by our new formula showed a prognostic power similar to the actual BNP levels. This equation will be useful, especially for a physician who is not familiar with NT-proBNP testing.

Accuracy of fully automated right ventricular quantification software with 3D echocardiography: direct comparison with cardiac magnetic resonance and semi-automated quantification software.

AIMS: The aim of this study was to determine the accuracy and reproducibility of a novel, fully automated 3D echocardiography (3DE) right ventricular (RV) quantification software compared with cardiac magnetic resonance (CMR) and semi-automated 3DE RV quantification software. METHODS AND RESULTS: RV volumes and the RV ejection fraction (RVEF) were measured using a fully automated software (Philips), a semi-automated software (TomTec), and CMR in 100 patients who had undergone both CMR and 3DE examinations on the same day. The feasibility of the fully automated software was 91%. Although the fully automated software, without any manual editing, significantly underestimated RV end-diastolic volume (bias: -12.6 mL, P < 0.001) and stroke volume (-5.1 mL, P < 0.001) compared with CMR, there were good correlations between the two modalities (r = 0.82 and 0.78). No significant differences in RVEF between the fully automated software and CMR were observed, and there was a fair correlation (r = 0.72). The RVEF determined by the semi-automated software was significantly larger than that by CMR or the fully automated software (P < 0.001). The fully automated software had a shorter analysis time compared with the semi-automated software (15 s vs. 120 s, P < 0.001) and had a good reproducibility. CONCLUSION: A novel, fully automated 3DE RV quantification software underestimated RV volumes but successfully approximated RVEF when compared with CMR. No inferiority of this software was observed when compared with the semi-automated software. Rapid analysis and higher reproducibility also support the routine adoption of this method in the daily clinical workflow.

Left ventricular and left atrial volume ratio assessed by three-dimensional echocardiography: Novel indices for evaluating age-related change in left heart chamber size.

We hypothesized that left ventricular and left atrial volume ratio (LVLAVR) assessed by three-dimensional echocardiography (3DE) reflects age- and gender-related change in left chamber size. We aimed to (1) determine the reference values of LVLAVR, (2) investigate their age and gender dependency, and (3) clarify which anthropometric and echocardiography parameters are closely associated with these indices. Both left ventricular (LV) and left atrial (LA) volume curves were obtained using 3DE speckle tracking analytical software, and the LVLAVR curve throughout one cardiac cycle was created, from which LVLAVR at ventricular end-diastole and at ventricular end-systole were determined in 313 healthy subjects (age, 20-85 years; 51% men). The mean values of LVLAVR at ventricular end-diastole and ventricular end-systole in male subjects were 5.74 ± 1.54 and 1.37 ± 0.35, respectively. Corresponding values in female subjects were significantly lower (5.20 ± 1.47, p = .003 and 1.13 ± 0.29, p < .001) than the values in male subjects. LVLAVR at ventricular end-diastole step wisely decreased to advanced aging, and had a highest F ratio compared with other left chamber volumetric parameters in both genders. LV mass and LA ejection fraction were significantly associated with LVLAVR at ventricular end-diastole. In contrast, LV mass and LV ejection fraction were significantly coupled with LVLAVR at ventricular end-systole. This study provides the reference values for LVLAVR from a relatively large number of healthy subjects. LVLAVR may be a sensitive parameter to reflect age- and gender-related change in LV and LA volumes. Further studies should be required to determine its clinical usefulness over traditional echocardiography parameters in various cardiovascular diseases.

Usefulness of Cibenzoline Stress Echocardiography to Determine Severity of Aortic Stenosis in a Patient with Combined Left Ventricular Outflow Tract Obstruction and Aortic Stenosis.

Left ventricular outflow tract obstruction (LVOTO) is sometimes accompanied by aortic stenosis (AS). Reliable estimation of the true severity of AS is often difficult because it cannot be discriminated from dual stenosis. A 75-year-old woman was referred to our hospital due to traumatic hemopneumothorax with exertional dyspnea. Echocardiography revealed AS and LVOTO by chance. A continuous Doppler echocardiography revealed a late-systolic peaking dagger-shaped profile with a 6.0 m/s of peak jet velocity across the LVOT and aortic valve, but it was difficult to discriminate between the coexisting peak flows. For an accurate evaluation of AS, we performed landiolol (short acting beta-blocker) and cibenzoline (Na+ channel-blocking agent) stress echocardiography with simultaneous recordings of both left ventricular and aortic pressure by catheter examination. Cibenzoline successfully eliminated the LVOTO, but landiolol did not. Cibenzoline stress echocardiography enabled us to evaluate the AS severity as less than moderate, resulting in proper decision-making. The findings in this case clearly showed that cibenzoline stress echocardiography has a potential utility for determining AS severity in a patient with coexistent dynamic LVOTO.

[Difficulties in distinguishing abnormal intensities associated with convulsion from tumor on MRI: a case report].

A 48-year-old man was admitted to our department with generalized convulsive seizures followed by recurrent partial clonic convulsions in the left face and arm. Convulsions stopped temporarily after administration of diazepam, fosphenytoin, and levetiracetam. However, frequent partial seizures occurred repeatedly and general anesthesia was required to control seizures. Diffusion-weighted and T2-weighted images revealed a high-intensity lesion in the right frontal lobe. A tumor-like area in the white matter showed high intensity on T2-weighted images with ring enhancement on gadolinium-enhanced T1-weighted images. An area of frontal cortex near the tumor was also enhanced. Brain surgery was performed for the purposes of diagnosis, seizure control and tumor resection. Histological findings demonstrated oligodendroglioma in the ring-enhancing area, but not in the frontal cortex. This fact indicated that contrast enhancement of the frontal cortex was caused by status epilepticus. It is important to recognize that status epilepticus could cause contrast enhancement on magnetic resonance imaging.

Intracholecystic Papillary Neoplasms Are Distinct From Papillary Gallbladder Cancers: A Clinicopathologic and Exome-sequencing Study.

Although intracholecystic papillary neoplasms (ICPNs) have been increasingly recognized, their features remain unclear because of the lack of standardized definition. This study aimed to elucidate clinicopathologic and genetic features of ICPNs using stringent diagnostic criteria. On the basis of the recently proposed criteria, gallbladder neoplasms showing delicate papillary growth were diagnosed as ICPNs, while polypoid papillary adenocarcinomas arranged in a complex architecture were categorized as papillary gallbladder cancers (GBCs). Clinicopathologic features were compared among ICPNs (n=7), papillary GBCs (n=24), and nonpapillary GBCs (n=44). Whole-exome and validation Sanger sequencing was also conducted. Gross mucin hypersecretion was detected in 3/7 ICPNs (43%), 1/24 papillary GBCs (4%), and 1/44 nonpapillary GBCs (2%) (P<0.001). All patients with ICPN lacked lymphovascular invasion and nodal metastasis, while these features were occasionally observed in patients with papillary or nonpapillary GBC (13% to 59%). ICPNs were less advanced than papillary and nonpapillary GBCs (P<0.001) with all cases of ICPNs being recurrence-free. Whole-exome and Sanger sequencing identified somatic mutations in STK11 (a causative gene of Peutz-Jegher syndrome; n=3), CTNNB1 (n=2), and APC (a gene of familial adenomatous polyposis; n=1) in ICPNs, while those alterations were exceptional in papillary and nonpapillary GBCs. ICPNs more commonly showed cytoplasmic and/or nuclear expressions of ß-catenin than papillary and nonpapillary GBCs. In conclusion, the histology-based classification of gallbladder papillary neoplasms is useful for identifying ICPNs that share clinicopathologic features with the pancreatic counterpart. ICPNs meeting the criteria were genetically distinct from papillary and nonpapillary GBCs, with STK11, CTNNB1, and APC being identified as major driver genes for ICPNs.

Optimal Number of Heartbeats Required for Representing Left Chamber Volumes and Function in Patients with Rate-Controlled Atrial Fibrillation.

BACKGROUND: The optimal number of heartbeats required for representing left heart chamber function in patients with atrial fibrillation (AFib) has not been extensively studied. METHODS: To determine the optimal number, we performed an automated quantification analysis of three-dimensional echocardiography (3DE) data sets in 93 patients with AFib for whom 10-20 consecutive one-beat full-volume 3DE data sets were acquired twice. We measured left ventricular end-diastolic volume (LVEDV), left ventricular ejection fraction (LVEF), and maximal left atrial volume (LAVmax) in each heartbeat; each parameter was averaged using a serial number of heartbeats randomly selected, and these values were compared with the averaged value obtained from the entire set of heartbeats. Coverage probability was determined using predefined cutoff values, the relative percentage differences in LVEDV and LAVmax of 5%, and the absolute percentage differences in LVEF of 5%. The optimal number of heartbeats was defined as the minimum number of heartbeats showing coverage probability ≥95%. RESULTS: Out of 93 patients, 73 patients had acceptable left ventricular contour casts (feasibility, 78%), and 79 patients had acceptable left atrial contour casts (feasibility, 85%). Using the aforementioned criteria, the minimum optimal number of heartbeats was nine for LVEDV and six for LAVmax. The corresponding minimum optimal number of heartbeats for LVEF was eight. However, the results varied as a function of the size of the chamber, the left ventricular function, and whether the AFib ventricular rate was controlled. CONCLUSIONS: In patients with AFib, the optimal number of heartbeats required to obtain representative chamber volumes and function was six to nine heartbeats randomly selected using 3DE automated quantification software.

Optimal threshold of three-dimensional echocardiographic fully automated software for quantification of left ventricular volumes and ejection fraction: Comparison with cardiac magnetic resonance disk-area summation method and feature tracking method.

AIMS: Novel fully automated left chamber quantification software for three-dimensional echocardiography (3DE) has a potential for reliable measurement of left ventricular (LV) volumes and ejection fraction (LVEF). However, the optimal setting of global LV endocardial border threshold has not been settled. METHODS AND RESULTS: We performed LV volumes and LVEF analysis using fully automated left chamber quantification software (Dynamic HeartModelA.I., Philips Medical Systems) in 65 patients who had undergone both 3DE and cardiac magnetic resonance (CMR) examinations on the same day. We recorded LV end-diastolic volume (LVEDV) and LV end-systolic volume (LVESV) according to the change in LV global border threshold settings from 0-point to 100-point with each increment of 10-point. These values were compared to the corresponding values of CMR with disk-area summation method and feature tracking (FT) method. Coverage probability (CP) was calculated as an index of accuracy and reliability. Fully automated software provided LV volumes and LVEF in 57 patients (Feasibility: 88%). LVEDV and LVESV increased steadily according to the increase in border threshold and reached minimal bias when border threshold setting was 80 against CMR disk-summation method and 90 against CMR FT method. Corresponding CP of LVEF was 0.74 and 0.84 against disk-area summation method and FT method. CONCLUSIONS: With CMR values as a reference, LV endocardial border threshold value can be set around 80 to 90 with the same number of LV end-diastole and end-systole threshold to approximate LVEDV, LVESV and LVEF with clinically acceptable CP values of LVEF.

Histological and molecular characterization of intrahepatic bile duct cancers suggests an expanded definition of perihilar cholangiocarcinoma.

BACKGROUND: Growing evidence has suggested that intrahepatic cholangiocarcinoma (iCCA) can be classified into small- and large-duct types. The present study aimed to elucidate how large-duct iCCA is similar and dissimilar to perihilar cholangiocarcinoma (pCCA). METHODS: The study cohort consisted of iCCA (n = 58) and pCCA (n = 44). After iCCA tumors were separated into small- (n = 36) and large-duct (n = 22) types based on our histologic criteria, genetic statuses of the three types of neoplasms were compared. Locations of iCCA were plotted on a three-dimensional image and their distances from the portal bifurcation were measured. RESULTS: Large-duct iCCA was distinct from small-duct iCCA in terms of frequency of bile duct reconstruction required, perineural infiltration, and survival, with these features more similar to pCCA. Large-duct iCCA and pCCA more frequently had the loss of SMAD4 expression and MDM2 amplifications than small-duct iCCA, whereas the loss of BAP1 expression and IDH1 mutations were mostly restricted to small-duct iCCA. From imaging analysis, most tumors of large-duct iCCA were present around the second branches of the portal vein. CONCLUSION: Large-duct type iCCA shared the molecular features with pCCA, and it may be reasonable to expand the definition of pCCA to include cancers originating from the second bile duct branches.

Interleukin-33 overexpression reflects less aggressive tumour features in large-duct type cholangiocarcinomas.

AIMS: The aim of the present study was to elucidate the clinicopathological significance of interleukin (IL)-6 and IL-33 expression in intrahepatic cholangiocarcinomas (iCCAs) and perihilar cholangiocarcinomas (pCCAs). METHODS AND RESULTS: IL-6 and IL-33 mRNA expression levels were examined in iCCAs (n = 55) and pCCAs (n = 32) by the use of quantitative real-time polymerase chain reaction and a highly sensitive in-situ hybridisation protocol (RNAscope), and expression levels were correlated with clinicopathological features. According to a recently proposed classification scheme, iCCAs were separated into small-duct (n = 33) and large-duct (n = 22) types. IL-6 and IL-33 expression levels were higher in large-duct iCCAs and pCCAs than in small-duct iCCAs, and there was a positive correlation between the expression levels of these cytokines. Double in-situ hybridisation/immunostaining showed that IL-6 mRNA was expressed in actin-positive (myo)fibroblasts, whereas IL-33 mRNA was mainly produced by CD31-positive endothelial cells. With the average expression level as a cut-off point, cases were classified as IL-6high and IL-6low or IL-33high and IL-33low . In the combined cohort of large-duct iCCAs and pCCAs, IL-6high and IL-6low cholangiocarcinomas shared many features, whereas IL-33high cases had less aggressive characteristics than IL-33low cases, as shown by lower tumour marker concentrations, smaller tumour sizes, less common vascular invasion, lower pT stages, and higher lymphocyte/monocyte ratios in blood. KRAS mutations were slightly less common in IL-33high cases than in IL-33low cases (9% versus 29%; P = 0.061). The strong expression of IL-33 in tissue appeared to be an independent favourable prognostic factor. CONCLUSIONS: IL-33high cholangiocarcinomas may represent a unique, less aggressive carcinogenetic process of the large bile ducts.

Transbronchial lung biopsy for the diagnosis of IgG4-related lung disease.

AIMS: The diagnosis of IgG4-related disease (IgG4-RD) requires a multidisciplinary approach, in which histology plays an important role. Although a diagnosis was previously established by the use of surgically resected specimens, there is increasing clinical demand to diagnose this systemic condition by the use of biopsies. The aim of the present study was to elucidate how useful transbronchial lung biopsies (TBLBs) are for this diagnostic purpose. METHODS AND RESULTS: The study cohort consisted of 20 consecutive patients diagnosed with IgG4-RD in other organs who underwent TBLB for potential pulmonary involvement. One case showing multiple granulomas suggestive of other conditions was excluded. Seven of the remaining 19 cases (37%) showed apparently normal lung tissue, indicating a sampling error, and 12 (63%) had microscopic abnormalities. Nine cases (47%) with a dense lymphoplasmacytic infiltrate met the number and ratio criteria for IgG4-positive plasma cell infiltration (>20 cells/high-power field, and an IgG4/IgG-positive plasma cell ratio of >40%). Obliterative phlebitis and storiform fibrosis were observed in one case each. In 43 control cases of various inflammatory conditions, tissue IgG4 elevations appeared to be uncommon, with only two cases (5%) each meeting the number or ratio criterion, and one case (2%) fulfilling both. All control cases with tissue IgG4 elevations were of eosinophilic pneumonia. CONCLUSIONS: Transbronchial lung biopsies provided histological findings that were supportive for the diagnosis of IgG4-RD in 47% of cases, with 98% diagnostic specificity. Therefore, they have potential as a useful and acceptable diagnostic approach for IgG4-related lung disease.

Idiopathic multicentric Castleman's disease: a clinicopathologic study in comparison with IgG4-related disease.

The present study aimed to compare clinicopathologic features between idiopathic multicentric Castleman's disease (n=22) and IgG4-related disease (n=26). Histology was analyzed using lymph node and lung biopsies. The expression of IL-6 mRNA in tissue was also examined by in situ hybridization and real-time PCR. Patients with idiopathic multicentric Castleman's disease were significantly younger than those with IgG4-related disease (p<0.001). Splenomegaly was observed in only idiopathic multicentric Castleman's disease (p=0.002), while pancreatitis and sialo-dacryoadenitis were restricted to IgG4-related disease (both p<0.001). Serum IgG4 concentrations were commonly elevated at >135 mg/dL in both groups (p=0.270). However, the IgG4/IgG ratio in IgG4-related disease was significantly higher than that in Castleman's disease (p<0.001). Histologically, sheet-like plasmacytosis was highly characteristic of idiopathic multicentric Castleman's disease (p<0.001), while plasmacytic infiltration in IgG4-related disease was always associated with intervening lymphocytes. Similar to laboratory findings, the IgG4/IgG-positive plasma cell ratio, but not the IgG4-positive cell count, was significantly higher in IgG4-related disease (p=0.002). Amyloid-like hyalinized fibrosis was found in 6/8 lung biopsies (75%) of Castleman's disease. The over-expression of IL-6 mRNA was not confirmed in tissue samples of Castleman's disease by either in situ hybridization or quantitative real-time PCR. In conclusion, useful data for a differential diagnosis appear to be age, affected organs, the serum IgG4/IgG ratio, sheet-like plasmacytosis in biopsies, and the IgG4/IgG-positive cell ratio on immunostaining. Since IL-6 was not over-expressed in tissue of idiopathic multicentric Castleman's disease, IL-6 may be produced outside the affected organs, and circulating IL-6 may lead to lymphoplasmacytosis at nodal and extranodal sites.