Methionyl-tRNA synthetase and aminoacyl-tRNA synthetases interacting multi-functional protein-lacking exon 2 as potential diagnostic biomarkers for lung cancer

Cytological specimens from computed tomography (CT)-guided needle aspiration biopsy (CT-NAB) have relatively low sensitivity for lung cancer diagnosis. This study evaluated the usefulness of the dual immunofluorescence (IF) staining method using methionyl-tRNA synthetase (MARS), aminoacyl-tRNA synthetases interacting multi-functional protein-lacking exon 2 (AIMP2-DX2), and pan-cytokeratin (pan-CK) obtained from clinical specimens. One-hundred forty-five cytology specimens were prospectively collected from patients who underwent CT-NAB under the suspicion of lung cancer. The results of two combinations of MARS, AIMP2-DX2, and pan-CK dual IF staining were compared with those of conventional cytology by calculating the area under the curve (AUC). The results of combining dual IF with conventional cytology showed higher AUC than conventional cytology alone: cytology/MARS/AIMP2-DX2 (0.891 vs. 0.829, P = 0.003), cytology/MARS/pan-CK (0.916 vs. 0.829, P < 0.001), and cytology/AIMP2-DX2/pan-CK (0.877 vs. 0.829, P = 0.005). In specimens with non-diagnostic results in conventional cytology, MARS/AIMP2-DX2 dual IF staining showed sensitivity, specificity, and AUC of 60.0%, 86.4%, and 0.79, respectively. The dual IF staining method using two combinations of MARS, AIMP2-DX2, and pan-CK is an effective diagnostic tool that can improve the lung cancer diagnostic yield by complementing conventional cytology.ope

Budd-Chiari syndrome with multiple large regenerative nodules

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The Clinicopathological and Prognostic Significance of Nrf2 and Keap1 Expression in Hepatocellular Carcinoma

Nuclear factor E2-related factor2 (Nrf2) activation is associated with both cytoprotective effects and malignant behavior of cancer cells. This study aimed to evaluate the clinicopathological implications of the expression of Nrf2, pNrf2, and its regulator Keap1 in human hepatocellular carcinomas (HCCs). Tissue microarrays consisting of 285 surgically resected HCCs were immunohistochemically stained with pNrf2, Nrf2, Keap1, stemness-related markers (keratin 19 (K19), epithelial cell adhesion molecule (EpCAM)), carbonic anhydrase IX (CAIX), epithelial-mesenchymal transition (EMT)-related markers (ezrin, uPAR, E-cadherin), and p53, and the results were correlated with the clinicopathological features. pNrf2 expression was significantly associated with increased proliferative activity, as well as EpCAM, ezrin, p53, and CAIX expression and E-cadherin loss (p < 0.05, all). Strong cytoplasmic Nrf2 expression was associated with CAIX and ezrin expression (p < 0.05, both). Keap1 was associated with increased proliferative activity, portal vein invasion, EMT-related markers, and p53 expression in CAIX-negative HCCs (p < 0.05, all). Both pNrf2 and cytoplasmic Nrf2 expression were associated with decreased overall survival (p < 0.05, both), and cytoplasmic Nrf2 expression was an independent predictor of decreased overall survival on multivariate analysis (hazard ratio 4.15, p < 0.001). Both pNrf2 and cytoplasmic Nrf2 expression were associated with poor survival and aggressive behavior of HCC. In addition, Keap1 expression was also associated with aggressive HCC behavior in CAIX-negative HCCs, suggesting that Keap1 expression should be interpreted in the context of hypoxia status.ope

Prognostic clinicopathologic factors in carcinoma of unknown primary origin: a study of 106 consecutive cases

A heterogeneous group of cancers for which the site of origin remains occult after detailed investigations is defined as carcinomas of unknown primary origin (CUPs). Because patients with CUP have a dismal prognosis, we have analyzed CUPs to highlight the implication of clinicopathologic factors related with patient survival. A total of 106 consecutive cases of CUP were collected. A two-step strategy of immunohistochemistry to assess CUPs according NCCN Guidelines is used to separate carcinomatous tumors and subtype carcinomas. Median follow up of censored patients was 26 months. Median survival time of whole patients was 13 months (95% confidence interval [CI], 8.43 - 19.1 months), with one, two and five-year survival rate of 53.7%, 35.1%, and 30.5%, respectively. Factors related with shorter overall survival was adenocarcinoma histology (P=0.001), increased CA19-9 (P=0.003), increased CEA (P=0.047), increased LDH (P<0.001), CK20 positivity (P=0.002), presence of bone metastasis (P=0.017), metastasis not confined to the lymph nodes (P=0.015), unfavorable clinical group based predefined category (P=0.017), and patients with no treatment (P<0.001). Multivariable analysis with cox regression model revealed factors related with overall survival; cases belonged to Culine's poor risk group (HR, 3.88; 95% CI, 1.75-8.64; P=0.001) and CK20 positivity (HR, 3.31; 95% CI, 1.42-7.70; P=0.005). In conclusion, the CK20 expression profile is a prognostic factor in patients with CUP and initial stratification of patient with Culine's model may provide a prognostic information in these patients. Assessment of clinical implication of these factors in the context of site specific therapy needs to be evaluated.ope

Squash smear cytology of Langerhans cell histiocytosis

Squash smear cytology of Langerhans cell histiocytosis (LCH) has rarely been reported. We described squash cytological findings of cranial LCH. Additionally, based on recent data that suggests an association of LCH with either viral infection or genetic alteration, we investigated the presence of several viruses or mutation of TP53 and BRAF in LCH tissue samples. Intraoperative squash smears of a small tissue fragment excised from the lesion demonstrated a mixed population of eosinophils, neutrophils, small lymphocytes and a high content of histiocytes. The histiocytes possessed abundant dense cytoplasm with round cell shape and eccentrically located nuclei with fine chromatin, delicate nuclear membranes and prominent nuclear grooves, indentations and pseudoinclusions. The cytologic features were consistent with Langerhans cells (LCs). Subsequent histopathologic examination confirmed the diagnosis of LCH. Immunohistochemically, the LCs were positive for S-100, CD1a and langerin, but negative for adenovirus, CMV, EBV, HHV-8, HPV, HSV, SV 40 and p53. BRAF V600E mutation was absent. Our findings did not support the role of viruses and genetic abnormalities in the pathogenesis of LCH. In summary, the presence of a mixed population of inflammatory cells and a high content of histiocytes with characteristic cytomorphology, along with radiologic evidence and appropriate clinical findings, is highly suggestive of LCH on the intraoperative squash smears. Awareness of characteristic cytological features of LCH is necessary for rapid and accurate diagnosis. Squash smear cytology is a potentially useful tool in the intraoperative diagnosis of LCH.ope

Optimal reproduction of a porcine benign biliary stricture model using endobiliary radiofrequency ablation

The use of endobiliary radiofrequency ablation (RFA) to generate a benign biliary stricture (BBS) model has a significant reproducibility problem. The aims of this animal study were to create an optimal BBS model using endobiliary RFA and determine the best way to develop it. The first step was performed on the common bile duct (CBD) of 10 miniature pigs using endoscopic RFA with a target temperature-controlled mode (80 ℃, 7 W for 90 s). The second step was performed on the CBD of five miniature pigs to understand more about the time-dependent changes in BBS development and the causes of adverse events. Using the conditions and techniques identified in the previous steps, the third step was conducted to create an optimal BBS model in 12 miniature pigs. In the first trial, four out of 10 animals died (40%) after the procedure due to cholangitis-induced sepsis. Based on this, biliary obstruction was prevented in further steps by placing a biliary plastic stent after RFA application. Histologic examinations over time showed that a severe abscess developed at the RFA application site on the fifth day, followed by fibrosis on the tenth day, and completion on the twentieth day. In the third trial, 11 animals survived (91.7%), the average BBS fibrotic wall thickness was 1107.9 µm (763.1-1864.6 µm), and the degree of upstream biliary dilation was 14.4 mm (11.05-20.7 mm). In conclusion, endobiliary RFA combined with a biliary plastic stent resulted in a safe and reproducible BBS animal model.ope

WWC1 and NF2 Prevent the Development of Intrahepatic Cholangiocarcinoma by Regulating YAP/TAZ Activity through LATS in Mice

Hippo signaling acts as a tumor suppressor pathway by inhibiting the proliferation of adult stem cells and progenitor cells in various organs. Liver-specific deletion of Hippo pathway components in mice induces liver cancer development through activation of the transcriptional coactivators, YAP and TAZ, which exhibit nuclear enrichment and are activated in numerous types of cancer. The upstream-most regulators of Warts, the Drosophila ortholog of mammalian LATS1/2, are Kibra, Expanded, and Merlin. However, the roles of the corresponding mammalian orthologs, WWC1, FRMD6 and NF2, in the regulation of LATS1/2 activity and liver tumorigenesis in vivo are not fully understood. Here, we show that deletion of both Wwc1 and Nf2 in the liver accelerates intrahepatic cholangiocarcinoma (iCCA) development through activation of YAP/TAZ. Additionally, biliary epithelial cell-specific deletion of both Lats1 and Lats2 using a Sox9-CreERT2 system resulted in iCCA development through hyperactivation of YAP/TAZ. These findings suggest that WWC1 and NF2 cooperate to promote suppression of cholangiocarcinoma development by inhibiting the oncogenic activity of YAP/TAZ via LATS1/2.ope

Benign multicystic mesothelioma of appendiceal origin treated by hyperthermic intraperitoneal chemotherapy: A case report

Introduction and importance: Peritoneal benign cystic mesothelioma is a rare benign tumor that originates from a mesothelial proliferative lesion of the peritoneum. However, proper surgical management remains unclear due to its low incidence. We report a clinical case of peritoneal benign cystic mesothelioma treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC). Case presentation: A 60-year-old female who underwent laparoscopic appendectomy in 2015 presented with abdominal pain in right lower quadrant area. Computed tomography of the abdomen and pelvis revealed a ruptured appendiceal mucocele or mucinous neoplasm, and several seeding-like small nodules in the greater omentum and right peritoneum. Cytoreductive surgery followed by HIPEC was performed; right hemicolectomy and lymph node dissection, omentectomy, and right abdominal partial peritonectomy. HIPEC with mitomycin was conducted for 90 min and an anastomosis between the ileum and colon was made after HIPEC. The pathologic results revealed the colonic mass was a multi-loculated cyst lined by mesothelial cells containing amorphous eosinophilic fibrinoid material, which are common features of benign cystic mesothelioma. Clinical discussion: Peritoneal benign cystic mesothelioma is known as a borderline disease of mesothelial tumors. Because its etiology is unknown, treatment strategies are not determined. Conclusion: Cytoreductive surgery followed by HIPEC can be considered to treat peritoneal benign cystic mesothelioma and prevent its malignant transformation.ope

The dual role of transforming growth factor-beta signatures in human B viral multistep hepatocarcinogenesis: early and late responsive genes

Background/Aim Transforming growth factor-beta (TGF-β) has a dichotomous role, functioning as a tumor suppressor and tumor promoter. TGF-β signatures, explored in mouse hepatocytes, have been reported to predict the clinical outcomes of hepatocellular carcinoma (HCC) patients; HCCs exhibiting early TGF-β signatures showed a better prognosis than those with late TGF-β signatures. The expression status of early and late TGF-β signatures remains unclear in defined lesions of human B-viral multistep hepatocarcinogenesis. Methods The expression of TGF-β signatures, early and late responsive signatures of TGF-β were investigated and analyzed for their correlation in cirrhosis, low-grade dysplastic nodules (DNs), high-grade DNs, early HCCs and progressed HCCs (pHCCs) by real-time PCR and immunohistochemistry. Results The expression levels of TGF-β signaling genes (TGFB1, TGFBR1, TGFBR2 and SMAD4) gradually increased with the progression of hepatocarcinogenesis, peaking in pHCCs. The expression of early responsive genes of TGF-β (GADD45B, FBP1, CYP1A2 and CYP3A4) gradually decreased, and that of the late TGF-β signatures (TWIST and SNAI1) significantly increased according to the progression of multistep hepatocarcinogenesis. Furthermore, mRNA levels of TWIST and SNAI1 were well correlated with those of stemness markers, with upregulation of TGF-β signaling, whereas FBP1 expression was inversely correlated with that of stemness markers. Conclusions The enrichment of the late responsive signatures of TGF-β with induction of stemness is considered to be involved in the progression of the late stage of multistep hepatocarcinogenesis, whereas the early responsive signatures of TGF-β are suggested to have tumor-suppressive roles in precancerous lesions of the early stage of multistep hepatocarcinogenesis.ope

Duodenal Amyloidosis

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