Toshifumi Gabata

Hepatocellular carcinoma: signal intensity at gadoxetic acid-enhanced MR Imaging--correlation with molecular transporters and histopathologic features.

PURPOSE To analyze the correlation between signal intensity in the hepatobiliary phase of gadoxetic acid-enhanced magnetic resonance (MR) imaging and the expression of hepatocyte transporters with histopathologic features in hepatocellular carcinoma (HCC). MATERIALS AND METHODS Institutional ethics committee approval and informed consent were obtained. Forty surgically resected HCCs were classified as hypointense (n = 32) or iso- or hyperintense (n = 8) on the basis of findings in the hepatobiliary phase of gadoxetic acid-enhanced MR imaging. The following were compared between hypointense and iso- or hyperintense HCCs: the time-signal intensity curves at gadoxetic acid-enhanced MR imaging, the expression levels of seven transporters (four organic anion-transporting polypeptides [OATPs] and three multidrug-resistant proteins [MRPs]) at polymerase chain reaction (PCR) (for 22 nodules), results of immunostaining of OATP8, and histologic features. Statistical analysis (unpaired t test, Mann-Whitney test, chi(2) test, and Fisher exact test) was performed for each result. RESULTS On the time-signal intensity curves, hypointense HCCs showed a decreasing pattern, whereas iso- or hyperintense HCCs showed an increasing pattern after the dynamic phase. PCR revealed that expression of OATP8 (an uptake transporter) in hypointense HCCs was lower and that in iso- or hyperintense HCCs was higher than in background liver (P < .001). The expression level of MRP3 (a sinusoidal export transporter) showed a similar trend to that of OATP8 (P < .001). Immunostaining revealed that OATP8 expression was weak in hypointense HCCs, whereas it was sustained in iso- or hyperintense HCCs (P < .001). At histologic examination, a pseudoglandular proliferation pattern with bile plugs was more commonly observed in iso- or hyperintense HCCs than in hypointense HCCs (P = .01 for proliferation patterns and P = .006 for bile plugs). CONCLUSION The enhancement ratio of HCCs in the hepatobiliary phase of gadoxetic acid-enhanced MR imaging positively correlated with expression levels of OATP8 and MRP3, indicating that gadoxetic acid is taken up by OATP8 and excreted by MRP3.

IgG4-related lung and pleural disease: a clinicopathologic study of 21 cases.

Immunoglobulin G4 (IgG4)-related disorders can occur in the respiratory system. However, the clinicopathologic characteristics have not been well clarified. In this study, we examined clinical and pathologic features of, and follow-up data on, IgG4-related lung and pleural lesions. The patients group consisted of 17 males and 4 females with an average age of 69 years (range: 42 to 76). Pulmonary lesions in 16 patients and pleural lesions in 5 patients were examined. Histologically, all lesions showed diffuse lymphoplasmacytic infiltration. Irregular fibrosis and obliterative vascular changes were more common in solid areas. Nine cases (43%) had eosinophilic infiltration with more than 5 cells per high-power field. Immunostaining revealed numerous IgG4-positive plasma cells in inflamed areas. Sclerosing inflammation was distributed with intrapulmonary connective tissue. Pulmonary lesions showed a variety of morphologic changes according to the predominant area of inflammation. Serum IgG4 concentrations were elevated in 9 of 11 patients tested (average 6.9 g/L; range 0.3 to 18.0 g/L; normal range <1.35 g/L). Extra-pulmonary and extra-pleural IgG4-related lesions were identified in 9 patients (43%), and developed simultaneously or asynchronously during follow up. All patients treated with steroids responded, but some radiologic abnormalities remained in 3 patients. Interestingly, 1 patient was found to have a primary adenocarcinoma against a background of IgG4-related lung disease during follow up. In conclusion, IgG4-related diseases show a greater variety of pulmonary and pleural lesions than previously thought. It is important, therefore, to know the morphologic variety and clinicopathologic characteristics of this disorder.

Detection and characterization of focal liver lesions: a Japanese phase III, multicenter comparison between gadoxetic acid disodium-enhanced magnetic resonance imaging and contrast-enhanced computed tomography predominantly in patients with hepatocellular carcinoma and chronic liver disease.

Objectives:To prospectively evaluate the safety and efficacy of combined unenhanced and gadoxetic acid disodium (Gd-EOB-DTPA)-enhanced magnetic resonance (MR) imaging compared with unenhanced MR imaging and triphasic contrast-enhanced spiral computed tomography (CT) for the detection and characterization of focal liver lesions. Materials and Methods:The study was reviewed and approved by the institutional review board at each of the 15 centers involved in the study, and informed written consent was given by all patients. In total, 178 patients with suspected focal hepatic lesions (based, in most patients, on CT, tumor marker and ultrasound examinations) underwent combined MR imaging with a single, rapid injection of Gd-EOB-DTPA 0.025 mmol/kg, including T1-weighted dynamic and delayed MR images 20 to 40 minutes postinjection. Triphasic contrast-enhanced CT, the comparator examination, was performed within 4 weeks of MR imaging. Standard of references (SOR) were resection histopathology and intraoperative ultrasonography, or combined CT during arterial portography and CT hepatic arteriography; in cases where, although the major lesions were treated, some lesion(s) were not treated, follow-up superparamagnetic iron oxide-enhanced MR imaging was additionally performed. All images were assessed for differences in lesion detection and characterization (specific lesion type) by on-site readers and 3, blinded (off-site) reviewers. All adverse events (AEs) occurring within 72 hours after Gd-EOB-DTPA administration were reported. Results:Overall, 9.6% of patients who received Gd-EOB-DTPA reported 21 drug-related AEs. A total of 151 patients were included in the efficacy analysis. Combined MR imaging showed statistically higher sensitivity in lesion detection (67.5%–79.5%) than unenhanced MR imaging (46.5%–59.1%; P < 0.05 for all). Combined MR imaging also showed higher sensitivity in lesion detection than CT (61.1%–73.0%), with the results being statistically significant (P < 0.05) for on-site readers and 2 of 3 blinded readers. Higher sensitivity in lesion detection with combined MR imaging compared with CT was also clearly demonstrated in the following subgroups: lesions with a diameter ≤20 mm (lesions ≤10 mm: 38.0%–55.4% vs. 26.1%–47.3%, respectively; lesions 10–20 mm: 71.1%–87.3% vs. 65.7%–78.4%, respectively); in cirrhotic patients (64.5%–75.4% vs. 54.5%–70.3%, respectively); and in patients with hepatocellular carcinoma (66.6%–78.6% vs. 59.1%–71.6%, respectively). Combined MR imaging demonstrated a higher proportion of correctly characterized lesions (50.5%–72.1%) than unenhanced MR imaging (30.2%–50.0%; P < 0.05 for all), whereas there were no significant differences compared with CT (49.0%–68.1%), except for one blinded reader (P < 0.05). Conclusion:In this study, hepatocyte-specific Gd-EOB-DTPA was shown to be safe and to improve the detection and characterization of focal hepatic lesions compared with unenhanced MR imaging. When compared with spiral CT, Gd-EOB-DTPA enhanced MRI seems to be beneficial especially for the detection for smaller lesions or hepatocellular carcinoma underlying cirrhotic liver.

TG13 diagnostic criteria and severity grading of acute cholecystitis (with videos)

Since its publication in 2007, the Tokyo Guidelines for the management of acute cholangitis and cholecystitis (TG07) have been widely adopted. The validation of TG07 conducted in terms of clinical practice has shown that the diagnostic criteria for acute cholecystitis are highly reliable but that the definition of definite diagnosis is ambiguous. Discussion by the Tokyo Guidelines Revision Committee concluded that acute cholecystitis should be suspected when Murphy’s sign, local inflammatory findings in the gallbladder such as right upper quadrant abdominal pain and tenderness, and fever and systemic inflammatory reaction findings detected by blood tests are present but that definite diagnosis of acute cholecystitis can be made only on the basis of the imaging of ultrasonography, computed tomography or scintigraphy (HIDA scan). These proposed diagnostic criteria provided better specificity and accuracy rates than the TG07 diagnostic criteria. As for the severity assessment criteria in TG07, there is evidence that TG07 resulted in clarification of the concept of severe acute cholecystitis. Furthermore, there is evidence that severity assessment in TG07 has led to a reduction in the mean duration of hospital stay. As for the factors used to establish a moderate grade of acute cholecystitis, such as leukocytosis, ALP, old age, diabetes, being male, and delay in admission, no new strong evidence has been detected indicating that a change in the criteria used in TG07 is needed. Therefore, it was judged that the severity assessment criteria of TG07 could be applied in the updated Tokyo Guidelines (TG13) with minor changes. TG13 presents new standards for the diagnosis, severity grading and management of acute cholecystitis.Free full-text articles and a mobile application of TG13 are available via http://www.jshbps.jp/en/guideline/tg13.html.

Immunoglobulin G4–related Lung Disease: CT Findings with Pathologic Correlations

PURPOSE To retrospectively analyze radiologic findings of immunoglobulin G4 (IgG4)-related lung disease as correlated with pathologic specimens. MATERIALS AND METHODS This study was approved by the institutional review board, and all patients had consented to the use of their medical records for the purpose of research. This study included 13 patients with IgG4-related lung disease (nine men and four women; age range, 43-76 years). Computed tomographic (CT) findings were retrospectively analyzed with regard to the characteristics, shape, and distribution of the radiologic findings and were correlated with surgically resected or biopsy lung specimens in seven patients. Statistical analysis was not used in this study. RESULTS On the basis of the predominant radiologic abnormality, IgG4-related lung disease could be categorized into four major subtypes: solid nodular type having a solitary nodular lesion that included a mass (four patients); round-shaped ground-glass opacity (GGO) type characterized by multiple round-shaped GGOs (two patients); alveolar interstitial type showing honeycombing, bronchiectasis, and diffuse GGO (two patients); and bronchovascular type showing thickening of bronchovascular bundles and interlobular septa (five patients). Pathologically, solitary nodular lesions consisted of diffuse lymphoplasmacytic infiltration with fibrosis. Thickened bronchovascular bundles or interlobular septa and GGO on CT images pathologically corresponded to lymphoplasmacytic infiltration and fibrosis in peribronchiolar or interlobular interstitium and alveolar interstitium, respectively. The radiologic findings of honeycombing corresponded to disrupted alveolar structures and dilated peripleural air spaces. CONCLUSION IgG4-related lung disease manifested as four major categories of CT features. Pathologically, these features corresponded to IgG4-related sclerosing inflammation along the intrapulmonary connective tissue.

The uptake transporter OATP8 expression decreases during multistep hepatocarcinogenesis: correlation with gadoxetic acid enhanced MR imaging

ObjectivesTo clarify the changes in organic anion-transporting polypeptide 8 (OATP8) expression and enhancement ratio on gadoxetic acid-enhanced MR imaging in hepatocellular nodules during multistep hepatocarcinogenesis.MethodsIn imaging analysis, we focused on 71 surgically resected hepatocellular carcinomas (well, moderately and poorly differentiated HCCs) and 1 dysplastic nodule (DN). We examined the enhancement ratio in the hepatobiliary phase of gadoxetic acid enhanced MR imaging [(1/postcontrast T1 value−1/precontrast T1 value)/(1/precontrast T1 value)], then analysed the correlation among the enhancement ratio, tumour differentiation grade and intensity of immunohistochemical OATP8 expression. In pathological analysis, we focused on surgically resected 190 hepatocellular nodules: low-grade DNs, high-grade DNs, early HCCs, well-differentiated, moderately differentiated and poorly differentiated HCCs, including cases without gadoxetic acid-enhanced MR imaging. We evaluated the correlation between the immunohistochemical OATP8 expression and the tumour differentiation grade.ResultsThe enhancement ratio of HCCs decreased in accordance with the decline in tumour differentiation (P < 0.0001, R = 0.28) and with the decline of OATP8 expression (P < 0.0001, R = 0.81). The immunohistochemical OATP8 expression decreased from low-grade DNs to poorly differentiated HCCs (P < 0.0001, R = 0.15).ConclusionsThe immunohistochemical expression of OATP8 significantly decreases during multistep hepatocarcinogenesis, which may explain the decrease in enhancement ratio on gadoxetic acid-enhanced MR imaging.

TG13: Updated Tokyo Guidelines for the management of acute cholangitis and cholecystitis

In 2007, the Tokyo Guidelines for the management of acute cholangitis and cholecystitis (TG07) were first published in the Journal of Hepato-Biliary-Pancreatic Surgery. The fundamental policy of TG07 was to achieve the objectives of TG07 through the development of consensus among specialists in this field throughout the world. Considering such a situation, validation and feedback from the clinicians’ viewpoints were indispensable. What had been pointed out from clinical practice was the low diagnostic sensitivity of TG07 for acute cholangitis and the presence of divergence between severity assessment and clinical judgment for acute cholangitis. In June 2010, we set up the Tokyo Guidelines Revision Committee for the revision of TG07 (TGRC) and started the validation of TG07. We also set up new diagnostic criteria and severity assessment criteria by retrospectively analyzing cases of acute cholangitis and cholecystitis, including cases of non-inflammatory biliary disease, collected from multiple institutions. TGRC held meetings a total of 35 times as well as international email exchanges with co-authors abroad. On June 9 and September 6, 2011, and on April 11, 2012, we held three International Meetings for the Clinical Assessment and Revision of Tokyo Guidelines. Through these meetings, the final draft of the updated Tokyo Guidelines (TG13) was prepared on the basis of the evidence from retrospective multi-center analyses. To be specific, discussion took place involving the revised new diagnostic criteria, and the new severity assessment criteria, new flowcharts of the management of acute cholangitis and cholecystitis, recommended medical care for which new evidence had been added, new recommendations for gallbladder drainage and antimicrobial therapy, and the role of surgical intervention. Management bundles for acute cholangitis and cholecystitis were introduced for effective dissemination with the level of evidence and the grade of recommendations. GRADE systems were utilized to provide the level of evidence and the grade of recommendations. TG13 improved the diagnostic sensitivity for acute cholangitis and cholecystitis, and presented criteria with extremely low false positive rates adapted for clinical practice. Furthermore, severity assessment criteria adapted for clinical use, flowcharts, and many new diagnostic and therapeutic modalities were presented. The bundles for the management of acute cholangitis and cholecystitis are presented in a separate section in TG13.Free full-text articles and a mobile application of TG13 are available via http://www.jshbps.jp/en/guideline/tg13.html.

TG13 flowchart for the management of acute cholangitis and cholecystitis

We propose a management strategy for acute cholangitis and cholecystitis according to the severity assessment. For Grade I (mild) acute cholangitis, initial medical treatment including the use of antimicrobial agents may be sufficient for most cases. For non-responders to initial medical treatment, biliary drainage should be considered. For Grade II (moderate) acute cholangitis, early biliary drainage should be performed along with the administration of antibiotics. For Grade III (severe) acute cholangitis, appropriate organ support is required. After hemodynamic stabilization has been achieved, urgent endoscopic or percutaneous transhepatic biliary drainage should be performed. In patients with Grade II (moderate) and Grade III (severe) acute cholangitis, treatment for the underlying etiology including endoscopic, percutaneous, or surgical treatment should be performed after the patient’s general condition has been improved. In patients with Grade I (mild) acute cholangitis, treatment for etiology such as endoscopic sphincterotomy for choledocholithiasis might be performed simultaneously, if possible, with biliary drainage. Early laparoscopic cholecystectomy is the first-line treatment in patients with Grade I (mild) acute cholecystitis while in patients with Grade II (moderate) acute cholecystitis, delayed/elective laparoscopic cholecystectomy after initial medical treatment with antimicrobial agent is the first-line treatment. In non-responders to initial medical treatment, gallbladder drainage should be considered. In patients with Grade III (severe) acute cholecystitis, appropriate organ support in addition to initial medical treatment is necessary. Urgent or early gallbladder drainage is recommended. Elective cholecystectomy can be performed after the improvement of the acute inflammatory process.Free full-text articles and a mobile application of TG13 are available via http://www.jshbps.jp/en/guideline/tg13.html.

Hepatocarcinogenesis: Multistep Changes of Drainage Vessels at CT during Arterial Portography and Hepatic Arteriography—Radiologic-Pathologic Correlation

PURPOSE To clarify the changes that occur in drainage vessels of dysplastic nodules and hepatocellular carcinoma (HCC) during hepatocarcinogenesis by using computed tomography (CT) during arterial portography (CTAP) and CT during hepatic arteriography (CTHA), with histologic findings as the reference standard. MATERIALS AND METHODS Institutional ethics committee approval and informed consent were obtained. According to the findings at CTAP and CTHA, 46 surgically resected hepatocellular nodules were classified into three types: type A (n = 18) (equivalent or decreased portal perfusion compared with background liver at CTAP, decreased arterial perfusion, and no corona enhancement [perinodular contrast material drainage] at CTHA), type B (n = 13) (no portal perfusion, increased arterial perfusion, and thin (< or = 2-mm) corona enhancement), or type C (n = 15) (no portal perfusion, increased arterial perfusion, and thick (> 2-mm) corona enhancement). We compared the histopathologic features and microangioarchitecture between the types. RESULTS Type A nodules histologically consisted of dysplastic nodules and well-differentiated HCC; type B and C nodules were moderately differentiated HCC. Replacing growth was commonly observed in type A nodules, whereas compressing growth was more frequently seen in types B and C. Sixty percent of type C nodules had a fibrous capsule. There were significantly fewer intranodular hepatic veins in types B and C. Serial pathologic slices demonstrated continuity from intranodular capillarized sinusoids to hepatic veins in type A nodules and to surrounding hepatic sinusoids in type B nodules. In type C nodules, intranodular capillarized sinusoids were connected to extranodular portal veins either directly or through portal venules within the fibrous capsule. CONCLUSION Drainage vessels of HCC change from hepatic veins to hepatic sinusoids and then to portal veins during multistep hepatocarcinogenesis.

Delayed enhancement of fibrotic areas in hepatic masses : CT-pathologic correlation

We report a histological analysis of the areas of high density in the postequilibrium and delayed phase CT in 43 focal hepatic lesions. The cases consisted of 16 cholangiocellular carcinomas, 9 hepatocellular carcinomas (including a sclerosing type of hepatocellular carcinoma and a combined hepatocellular-cholangiocellular carcinoma), 13 metastases, 2 granulomas, an inflammatory pseudotumor, a malignant lymphoma, and an epithelioid hemangioendothelioma. Computed tomography was performed after hepatic angiography using 40-50 g iodine and arteriographic CT using 35 g iodine. The areas of delayed enhancement corresponded histologically to fibrotic tissues, from inflammatory change to extensive fibrosis.