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Graphical abstract, Highlights • CNCs have potential to stabilize curcuminoid content for at least 12-months. • CNCs are safe in appropriate dose as low and medium doses of toxicity testing. • High dose of CNCs could produce toxicity in blood parameters and histopathology. • Most altered parameters in chronic toxicity test could recover within 28 days. • CNCs have very low toxicity in non-clinical trials and are ready for clinical study., We recently developed a modified solid dispersion of curcumin-loaded nanocomplexes (CNCs) in gums which promoted the prolonged and sustained release of curcumin. However, its safety assessment has not yet been investigated. Here, acute and chronic toxicities of CNCs were assayed using mice and hamsters. CNCs were orally administered to the animals. Doses of CNCs used for acute toxicity testing were 0.1, 1.1, 11.0 g/kg body weight for mice and 0.2, 2.1 and 21.4 g/kg body weight for hamsters. Doses of CNCs for chronic toxicity testing were 0.09, 0.27, 0.8 g/kg body weight/day for mice and 0.18, 0.54 and 1.61 g/kg body weight/day for hamsters. This regimen was followed daily for 6 months. Low and medium doses of CNCs did not induce any side effects in acute and chronic toxicity tests in either animal species. However, in acute toxicity testing, the organ-weight to body-weight ratio of spleen was significantly increased in mice treated with 11 g/kg body weight along with elevated levels of some biochemical parameters. There was a significant increase in organ-weight to body-weight ratios of stomach, liver and heart in hamsters treated with 21.4 g/kg body weight, but no elevated levels of biochemical parameters. Oral LD50 of CNCs in mice and hamsters were 8.9 and 16.8 g/kg body weight (equivalent to 2.5 and 4.7 g curcumin/kg body weight), respectively. Daily CNCs high-dose treatment for 6 months significantly increased organ-weight to body-weight ratios of stomach and intestine in mice and of lung and heart in hamsters. Elevated levels of glucose, total protein, ALT, AST and globulin in mice, and increased levels of AST, but decrease in cholesterol, in hamsters were concurrently observed with inflammation in liver and lung. These abnormalities were resolved within 28 days after cessation of treatment. The no-observed-adverse-effect level of CNCs was determined at 0.27 and 0.54 g/kg body weight/day in mice and hamsters. In conclusion, toxicity of high-dose CNCs treatment was graded as very low, possibly due to the components of the nanocomplex.

Background To evaluate the role of diffusion MRI in differentiating pediatric posterior fossa tumors and determine the cut-off values of ADC ratio to distinguish medulloblastoma from other common tumors. Methods We retrospectively reviewed MRI of 90 patients (7.5-year median age) with pathologically proven posterior fossa tumors (24 medulloblastoma, 7 ependymoma, 4 anaplastic ependymoma, 13 pilocytic astrocytoma, 30 diffuse intrinsic pontine glioma (DIPG), 4 ATRT, 3 diffuse astrocytoma, 2 high grade astrocytoma, 2 glioblastoma, and 1 low grade glioma). The conventional MRI characteristics were evaluated. Two readers reviewed DWI visual scale and measured ADC values by consensus. ADC measurement was performed at the solid component of tumors. ADC ratio between the tumors to cerebellar white matter were calculated. Results The ADC ratio of medulloblastoma was significantly lower than ependymoma, pilocytic astrocytoma and DIPG. The ADC cut-off ratio of ≤ 1.115 allowed discrimination medulloblastoma from other posterior fossa tumors with sensitivity, specificity, PPV and NPV of 95.8%, 81%, 67.6% and 97.9%, respectively. ADC ratio cut-off level to differentiate medulloblastoma from ependymoma was ≤ 0.995 with area under the curve (AUC)= 0.8693. ADC ratio cut-off level for differentiate medulloblastoma from pilocytic astrocytoma at ≤ 1.17 with AUC = 0.9936. ADC cut-off level for differentiate medulloblastoma from DIPG at ≤ 1.195 with AUC = 0.9681. The ADC ratio was correlated with WHO grading by the lower ADC ratio associated with the higher grade. Furthermore, High DWI visual scale was associated with high grade tumor. Conclusion Diffusion MRI has a significant role in diagnosis of pediatric posterior fossa tumors. ADC ratio can be used to distinguish medulloblastoma from other posterior fossa tumor with good level of diagnostic performance.

High mobility group nucleosome-binding protein 3 (HMGN3), a member of the HMGN family, modulates the structure of chromatin and regulates transcription through transcription factors. HMGN3 has been implicated in the development of various cancers; however, the underlying mechanisms remain unclear. We herein demonstrated that the high expression of HMGN3 correlated with the metastasis of liver fluke infection-induced cholangiocarcinoma (CCA) in patients in northeastern Thailand. The knockdown of HMGN3 in CCA cells significantly impaired the oncogenic properties of colony formation, migration, and invasion. HMGN3 inhibited the expression of and blocked the intracellular polarities of epithelial regulator genes, such as the CDH1/E-cadherin and TJAP1 genes in CCA cells. A chromatin immunoprecipitation sequencing analysis revealed that HMGN3 required the transcription factor SNAI2 to bind to and repress the expression of epithelial regulator genes, at least in part, due to histone deacetylases (HDACs), the pharmacological inhibition of which reactivated these epithelial regulators in CCA, leading to impairing the cell migration capacity. Therefore, the overexpression of HMGN3 represses the transcription of and blocks the polarities of epithelial regulators in CCA cells in a manner that is dependent on the SNAI2 gene and HDACs.

Background: Curcumin-loaded nanocomplexes (CNCs) previously demonstrated lower toxicity and extended release better than is the case for free curcumin. Here, we evaluated the efficacy of CNCs against opisthorchiasis-associated cholangiocarcinoma (CCA) in hamsters. Method: Dose optimization (dose and frequency) was performed over a one-month period using hamsters, a model that is widely used for study of opisthorchiasis-associated cholangiocarcinoma. In the main experimental study, CCA was induced by a combination of fluke, Opisthorchis viverrini (OV), infection and N-nitrosodimethylamine (NDMA) treatment. Either blank (empty) nanocomplexes (BNCs) or different concentrations of CNCs (equivalent to 10 and 20 mg cur/kg bw) were given to hamsters thrice a week for five months. The histopathological changes, biochemical parameters, and the expression of inflammatory/ oncogenic transcription factors were investigated.Results: The optimization study revealed that treatment with CNCs at a dose equivalent to 10 mg cur/kg bw, thrice a week for one month, led to a greater reduction of inflammation and liver injury induced in hamsters by OV+NDMA than did treatments at other dose rates. Oral administration with CNCs (10 mg cur/kg bw), thrice a week for five months, significantly increased survival rate, reduced CCA incidence, extent of tumor development, cholangitis, bile-duct injury and cholangiofibroma. In addition, this treatment decreased serum ALP and ALT levels and suppressed expression of oncogenic transcription factors including NF- κB and FOXM1. Conclusion: CNCs (10 mg cur/kg bw) attenuate the progression of fluke-related CCA in hamsters.

To evaluate the effectiveness of diffusion-weighted imaging (DWI) and susceptibility-weighted imaging (SWI) for differentiation between germinoma and other pineal region tumors.This retrospective study consisted of 72 patients with pathologically proven pineal region tumors between January 2010 and August 2020. Tumors were classified as germinomas (40), non-germinomatous germ cell tumors (11) (NGGCT), pineal parenchymal tumors (10) (PPT), and other types of tumors (11). Visual scale score, ADC values and SWI intratumoral susceptibility signal (ITSS) score were analyzed and compared to histopathology data.The mean apparent diffusion coefficient (ADCmean) and minimum apparent diffusion coefficient (ADCmin) ratio of germinoma were significantly lower than NGGCT. ADCmean or ADCmin cut-off ratio of ≤ 1.48 or ≤ 1.32 allowed for discrimination between germinoma and NGGCT with sensitivity and specificity of 100 % and 63.6 %. An ADCmin cut-off ratio of ≥ 0.93 allowed for discrimination between germinoma and PPT with sensitivity and specificity of 60 % and 80.0 %. ADCmin cut-off ratio of ≤ 1.15 allowed for discrimination of germinoma from other types of tumors with sensitivity and specificity of 87.5 % and 54.5 %.ADC ratio can differentiate germinoma from other types of pineal region tumors. Our initial results suggest that ITSS score was not significantly correlated with specific histology subtype.

Background: To compare diagnostic accuracy between DWI visual scale assessment and ADC value measurement of solid portion of the tumor in grading gliomas. Methods: This retrospective study included 38 patients who had pathologically proven gliomas between January 2013 and August 2018 with 18 low grade and 20 high grade tumors. All patients underwent MRI and biopsy. Two readers reviewed DWI visual scale independently. Disagreement was resolved by consensus. One reviewer measured ADC value of entire solid part of the tumor in single axial slice with greatest dimension of tumor which was chosen by consensus. Two data sets of visual scale and ADC value were analyzed and comparison of diagnostic accuracy in glioma grading was done by using area under the curve (AUC) of receiver operating characteristic curve (ROC). Results: Visual scale and ADC value could be used to distinguish between low and high grade gliomas with a statistically significant difference. (P-value 0.002 and

Supplemental digital content is available in the text., BACKGROUND Clinical assessment of indeterminate burn wounds has been reported to yield poor accuracy, even when performed by burn experts. Indocyanine green (ICG) dye angiography has been found to be highly accurate in assessing burn depth, but there is still limited evidence of its use in indeterminate burn wounds. This study aims to compare the accuracy of ICG angiography to that of clinical assessment in assessing indeterminate burn wounds. METHODS This is a prospective, multicentered, triple-blinded, experimental study. Participants were stable patients, admitted to the hospital with burn wounds of indeterminate depth. The burn wounds were clinically assessed by an attending plastic surgeon. ICG angiography was performed and evaluated by another surgeon. Tissue biopsies were obtained and sent for histological study to be assessed as the gold standard. RESULTS In the 30 burn sites that were assessed, the accuracy of ICG angiography was 100.0%, compared with 50.0% for clinical assessment (p < 0.001). Clinical assessment yielded a sensitivity of 33.3% and specificity of 66.7%, while ICG angiography yielded both a sensitivity and specificity of 100.0%. Therefore, the number needed to treat for using ICG angiography in indeterminate burn wounds was two. CONCLUSION Indocyanine green angiography yields a significantly higher accuracy than clinical assessment in indeterminate burn wounds. This intervention can, thus, be a useful tool to aid clinical judgment. TRIAL REGISTRATION Thai Clinical Trials Registry, number TCTR20170821001. LEVEL OF EVIDENCE Diagnostic test, level I.

Forkhead box M1 (FOXM1) is a transcriptional factor which plays an important role in oncogenesis. Four FOXM1 isoforms, FOXM1a, FOXM1b, FOXM1c and FOXM1d, are known so far. Different FOXM1 isoforms influence progression of cancer in different cancer types. In this study, the FOXM1c isoform and its impact in cholangiocarcinoma (CCA) was identified. FOXM1c was found to be the predominant isoform in patient-CCA tissues and cell lines. Detection of FOXM1c expression in CCA tissues reflected the worse prognosis of the patients, namely the advanced stage and shorter survival. Suppression of FOXM1 expression using siRNA considerably reduced migration and invasion abilities of CCA cell lines. RNA sequencing analysis revealed claudin-1 as a target of FOXM1. FOXM1 exhibited a negative correlation with claudin-1 expression which was demonstrated in patient CCA tissues and cell lines. FOXM1 may be a potential target for therapeutic treatment of the metastatic CCA., FOXM1; Cholangiocarcinoma; Metastasis; RNA sequencing

Cholangiocarcinoma (CCA) is an uncommon malignancy but occurs as a leading cancer in both sexes in Northeastern Thailand, an endemic area of a known CCA risk factor, the liver fluke (Opisthorchis viverrini). CCA is considered as an epidemic cancer in this geographic region, albeit based on serology testing, at least one fifth of CCA cases show no previous chronic exposure to fluke infestation. CCAs are adenocarcinoma that can present with various clinical features and differentiation. The histogenesis of the small bile duct type CCA is from hepatic stem cells in the canals of Hering and bile ductules, whereas the large bile duct type CCA is from bile duct stem cells located in peribiliary glands, embedded in the wall of large bile ducts. CCAs in the endemic area of liver flukes are primarily of the large bile duct type, which have two major phenotypes: tubular adenocarcinoma (accounting for two third of cases) and papillary carcinoma (accounting for the remaining third). The prognosis of CCA is dismal, with only half of patients surviving more than a year. Of note, the papillary phenotype of CCA has a better prognosis, which is attributable to the exophytic nature of the tumors, their late invasion into liver parenchyma, and ultrasonography screening being capable of detecting disease at an early stage. In this chapter, we discuss these and other aspects of fluke-associated CCA.

Background/aim Pyruvate kinase M2 (PKM2) is an enzyme that is predominantly overexpressed in various types of cancer. The role of PKM2 in liver fluke-associated cholangiocarcinoma (CCA) remains unclear. This study aimed to investigate the antitumor activity of shikonin, a PKM2 inhibitor, in CCA cells. Materials and methods Immunohistochemistry and immunoblotting were used to determine PKM2 expression in CCA tissues and cells. Antiproliferative effects of shikonin were evaluated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, colony-formation and trypan blue exclusion assays. The anti-metastatic activity of shikonin was determined using the Boyden chamber assay. Mechanisms by which shikonin inhibited CCA progression were determined. Results PKM2 was overexpressed in CCA compared to normal bile duct epithelial cells. Shikonin significantly inhibited growth, and migration of CCA cells while inducing their death. A mechanistic study revealed that antitumor effects of shikonin in CCA cells depended on increased production of reactive oxygen species. Conclusion Shikonin may be a novel therapeutic agent for patients with CCA.

Objectives Meningioma is one of the most common primary intracranial tumors. Diagnosis by imaging is not difficult. However evaluation of tumor consistency is an important factor affecting the surgical outcomes. The purpose of our study is to discover the relationship of different findings on pre-operative MRI, with a focus on detailed architectures, and different degrees of intra-operative stiffness of meningioma. Consistency of meningioma is also analyzed in compression to semi-quantitative pathological grading of fibrosis. Patients and Methods Sixty patients who underwent pre-operative MRI and primary surgery at our hospital were included in prospective fashion. Pre-operative MRI parameters, including general data and detailed internal architectures, were recorded. Intra-operative grading of tumor consistency was performed by the neurosurgeon. Pathological report according to WHO 2007 was performed with additional semi-quantitative grading of fibrosis. This study is focused on correlation of operative grade and MRI findings. Results Meningioma with hard consistency shows significant correlation with several features including en plaque appearance (p = 0.0427), higher ADC value (p = 0.0046) and ratio (p = 0.0016), absent of prominent enhanced rim (p = 0.0306), absent of enostotic spur (p = 0.0040) and absent of vascular core (p = 0.0133) in univariate analysis but no significant correlation is found in multivariate analysis in all except ADC ratio. Higher ADC ratio increase relative risk of hard consistency of meningioma by a factor of 41.22 (ORs = 41.22; 95%CI = 1.19–1426.24, P = 0.04). Good to very good inter-rater agreements are found. No significant correlation between tumor consistency and WHO grading was shown (p = 0.606). However, near significant p-value (p = 0.055) is found with increase degree of fibrosis in pathology as increase degree of tumor consistency. Conclusion We found that en plaque appearance, higher ADC value and ADC ratio, absent of prominent capsular enhancement and absent of vascular core were suggestive of hard consistency in univariate analysis but not independent factors. Additionally, semi-quantitative pathological grading of fibrosis showed near significant correlation with tumor consistent.

Background and objectives: Sialylation plays important roles in tumor progression. Our present study aimed to demonstrate the alteration of sialylation and its role in cholangiocarcinoma (CCA). Materials and Methods: The &alpha, 2,3- and &alpha, 2,6-sialylation in CCA tissue was analyzed by lectin-histochemistry using Maackia amurensis lectin-II (MAL-II) and Sambucus nigra agglutinin (SNA). CCA cell lines were treated with the pan-sialylation inhibitor 3Fax-peracetyl-Neu5Ac (3F-Sia) followed by proliferation and chemosensitivity assays. Results: MAL-II binding &alpha, 2,3-Sialylated Glycan (MAL-SG) and SNA binding &alpha, 2,6-Sialylated Glycan (SNA-SG) were both elevated in CCA compared with hyperplastic/dysplastic (HP/DP) and normal bile ducts (NBD). The positive staining for MAL-SG or SNA-SG were found in 82% (61/74) of the CCA cases. Higher expression of MAL-SG in CCA was associated with shorter survival of the patients. The median survival of patients with high and low MAL-SG were 167 and 308 days, respectively, with overall survival of 233 days, suggesting the involvement of MAL-SG in CCA progression. MAL-SG expression of CCA cell lines was markedly decreased after treatment with 3F-Sia for 48 to 72 h. While proliferation of CCA cells were not affected by 3F-Sia treatment, their susceptibility to 5-fluorouracil (5-FU) was significantly enhanced. These results suggest that sialylation is involved in the development of 5-FU resistance and the sialylation inhibitor 3F-Sia can be used as a chemosensitizer for CCA. Conclusions: Sialylation is critically involved in the development of chemoresistance of CCA, and sialylation inhibitors may be used as a chemosensitizer in CCA treatment.

The involvement of chronic inflammation in cholangiocarcinoma (CCA) progression is well established. Cluster of differentiation 47 (CD47) is mutually expressed in various cancers and serves as a protective signal for phagocytic elimination. CD47 signaling blockage is a recent treatment strategy; however, little is known regarding CD47 in CCA. Therefore, the potential use of CD47 targeting in CCA was focused. CD47 was highly expressed in CCA compared to hepatocellular carcinoma (HCC). Disturbance of CD47-signal regulatory protein-α (SIRPα) interaction by blocking antibodies promoted the macrophage phagocytosis. The therapeutic potential of anti-CD47 therapy was demonstrated in liver metastatic model; alleviation of cancer colonization together with dense macrophage infiltrations was observed. The usefulness of anti-CD47 was emphasized by its universal facilitating macrophage activities. Moreover, increased production of inflammatory cytokines, such as IL-6 and IL-10, in macrophage exposed to CCA-conditioned media suggested that CCA alters macrophages toward cancer promotion. Taken together, interfering of CD47-SIRPα interaction promotes macrophage phagocytosis in all macrophage subtypes and consequently suppresses CCA growth and metastasis. The unique overexpression of CD47 in CCA but not HCC offers an exceptional opportunity for a targeted therapy. CD47 is therefore a novel target for CCA treatment.

Extramedullary hematopoiesis (EMH) suggests the presence of hematopoietic stem cells (HSC) outside bone marrow. EMH has been reported, albeit rarely, in pyogenic granuloma (PG), a polypoid lobular capillary hemangioma. However, statistical data have hitherto been lacking on the actual incidence of EMH in PG. Therefore, we here reviewed 157 consecutive cases using routine diagnostic surgical slides and found unequivocal EMH in 17 (10.8%). This indicates that EMH is a rather common finding in PG, which could thus have strong potential to be an important resource for the study of HSC.

To describe typical clinical and laboratory characteristics of severe fungal keratitis caused by Pythium insidiosum during the rainy season in Northeast Thailand and to report the efficacy of P. insidiosum vaccine in the treatment of Pythium keratitis.A series of hospital-based consecutive cases of Pythium keratitis were diagnosed and treated at Srinagarind Hospital (Khon Kaen University, Khon Kaen, Thailand). The clinical presentations, diagnostic tests, and management are described.Severe fungal keratitis caused by P. insidiosum was diagnosed in 5 eyes of 4 patients between May 2009 and July 2009. All cases had a history of fungal keratitis after being exposed to contaminated water. Upon slit-lamp examination, subepithelial and superficial stromal opacities were observed in a reticular pattern in all cases. Pythium insidiosum was identified and confirmed by both microbiological culture and polymerase chain reaction. Clinical worsening was detected after conventional treatment with antifungal agents. Therapeutic penetrating keratoplasty with either donor cornea or scleral graft was performed together with topical antifungal administration and P. insidiosum vaccination. Subsequent evisceration was performed in 1 eye.An outbreak of Pythium keratitis in Northeast Thailand was reported. Distinctive clinical features are a suggestive clue for early diagnosis. Combination treatment including topical antifungal agents, radical surgery, and P. insidiosum vaccine may be considered for the management of Pythium keratitis.

Lactate dehydrogenase A (LDHA), a key metabolic enzyme, plays a crucial role in the final step of anaerobic glycolysis. Overexpression of LDHA is observed in many human malignancies in association with tumor progression. The purpose of this study was to investigate LDHA expression pattern during carcinogenesis, its clinico-pathological association, and evaluate the prognostic value of LDHA in CCA patients. LDHA expression was investigated using immunohistochemistry technique in both hamster- (n=60) and human-CCA tissues (n=82). Plasma LDH from healthy control (n=40) and CCA patients (n=29) were determined using an enzymatic based assay. The association of LDHA expression with clinico-pathological findings and prognostic value were evaluated by statistical analysis. In the CCA hamster model, an increase of LDHA expression was associated with the progression of CCA-genesis. Higher LDHA overexpression was associated with shorter survival of CCA patients. Multivariate analysis indicated that LDHA expression including histological type and N stage of tumor were independent prognostic risk factor of patient's survival. However, there was no difference in plasma LDH level between CCA patients and healthy controls. LDHA expression is involved in cholangiocarcinogenesis. Overexpression of LDHA can be a marker of poor prognosis in CCA patients and it might be a potential target for CCA treatment.

Background The amount of dietary monosodium glutamate (MSG) is increasing worldwide, in parallel with the epidemics of metabolic syndrome. Parenteral administration of MSG to rodents induces obesity, hyperglycemia, hyperlipidemia, insulin resistance, and type 2 diabetes. However, the impact of dietary MSG is still being debated. We investigated the morphological and functional effects of prolonged MSG consumption on rat glucose metabolism and on pancreatic islet histology. Methods Eighty adult male Wistar rats were randomly subdivided into 4 groups, and test rats in each group were supplemented with MSG for a different duration (1, 3, 6, or 9 months, n=20 for each group). All rats were fed ad libitum with a standard rat chow and water. Ten test rats in each group were provided MSG 2 mg/g body weight/day in drinking water and the 10 remaining rats in each group served as non-MSG treated controls. Oral glucose tolerance tests (OGTT) were performed and serum insulin measured at 9 months. Animals were sacrificed at 1, 3, 6, or 9 months to examine the histopathology of pancreatic islets. Results MSG-treated rats had significantly lower pancreatic β-cell mass at 1, 6 and 9 months of study. Islet hemorrhages increased with age in all groups and fibrosis was significantly more frequent in MSG-treated rats at 1 and 3 months. Serum insulin levels and glucose tolerance in MSG-treated and untreated rats were similar at all time points we investigated. Conclusion Daily MSG dietary consumption was associated with reduced pancreatic β-cell mass and enhanced hemorrhages and fibrosis, but did not affect glucose homeostasis. We speculate that high dietary MSG intake may exert a negative effect on the pancreas and such effect might become functionally significant in the presence or susceptibility to diabetes or NaCl; future experiments will take these crucial cofactors into account.

Administration of praziquantel for treatment of liver fluke infection may affect the host, with mild and severe effects after treatment caused by host immune response. Therefore, we focused on the antioxidant property, inflammatory and anthelmintic effects of the traditional folk medicine, G. mangostana pericarp extract, in hamster opisthorchiasis. Syrian hamsters were divided into four groups: normal (control) (N); administered G. mangostana alone (GM); infected with Opisthorchis viverrini alone (OV); and infected with O. viverrini and administered G. mangostana extract for 1.5 months (OVGM). Hamster livers were collected 45 days after infection to determine histopathological changes, i.e. aggregation of inflammatory cells. The morphology of adult O. viverrini (body size and sizes of reproductive organs) was analyzed, as well as worm burden, eggs per worm and eggs per gram of feces. Toxicity was tested by kidney function (blood urea nitrogen and creatinine); the results demonstrated that G. mangostana had no renal toxic effect. ABTS radical-scavenging assay indicated that the extract had antioxidant property. Reduction in aggregation of inflammatory cells surrounding the hepatic bile duct, especially at the hilar region, was found in the OVGM group. Worm burden was similar in both infected groups (treated or untreated with G. mangostana), but the average size of adults in the OV group was larger than in the OVGM group; moreover, eggs per worm and eggs per gram of feces were also comparatively higher. The present study suggests that G. mangostana extract possesses anti-inflammatory and antioxidant properties and can interfere with parasite development by affecting adult size and egg production. This may be useful for controlling the spread of OV infection and other parasites in endemic areas.

CCD44, a transmembrane glycoprotein receptor, plays significant roles in cell migration, differentiation, and survival signaling which are important for both normal and cancer cells. In this study, we examined the expression of all isoforms of CD44 by immunohistochemistry in 3 cases of biliary cystadenoma, 15 cases of non-invasive cystadenocarcinoma (CAC) bile duct tumors, and 67 cases of the aggressive bile duct tumor, cholangiocarcinoma (CCA). Normal bile duct epithelia at different segments along the biliary tree did not express CD44. However, normal biliary cells of the large bile duct adjacent to tumor areas and dysplastic biliary cells in CCA tissues were positive. CD44 was not expressed in cystadenomas and the majority of CACs. Two CAC cases with short survival and the majority of CCA aberrantly expressed CD44. These observations suggest important roles for CD44 in the early stage of carcinogenesis and progression of bile duct cancer. Regardless of the type of bile duct tumor, CAC or CCA patients with positive CD44 expression in biliary epithelia had significant shorter survival than those with negative CD44. Aberrant expression of CD44 in CAC or CCA tissues may indicate an unfavorable patient outcome and may serve as a useful practical adjunct to conventional prognostic indicators for bile duct cancer.

Combination of Opisthorchis viverrini infection and other factors could drive cholangiocarcinoma (CCA) development in Southeast Asia. However, other CCA factors are obscure. Alcohol consumption is well known in the risk for several cancers, but there is no report in CCA development. Therefore, the present study was to clarify whether drinking alcohol increases the liver pathology of Opisthorchis viverrini (OV) infection which may be the CCA risk. Experimental Syrian hamsters were divided into two groups: (1) infected with OV alone (OV); and (2) infected with OV plus administration of drinking alcohol (OV + ALC) for various lengths of time, i.e., 1, 2, 3, and 6 months. Hamster livers were collected for analysis of histopathological changes through hematoxylin and eosin, Sirius red, and immunohistostaining for proliferating cell nuclear antigen (PCNA) and cytokeratin 19 (CK19). Syrian hamster sera were used for liver function tests. Observed histopathological changes consisted primarily of aggregations of inflammatory cells surrounding the hepatic bile duct, especially at the hilar region, in both OV and OV + ALC groups; however, there was a difference in virulence. The OV + ALC group showed greater severity than the OV group. Moreover, in addition to aggregations of inflammatory cells, new bile duct formation (including hepatic cell death) was observed in subcapsular hepatic tissue. Bile duct proliferation, as determined by positive immunohistochemical staining for CK19 and PCNA, was correlated with the histopathology. Increased fibrosis was observed in subcapsular liver tissue. The present study suggests that alcohol consumption can exacerbate cholangiofibrosis, cholangitis, and lithiasis, which are risk factors for CCA.

Extramedullary hematopoiesis (EMH) suggests the presence of hematopoietic stem cells (HSC) outside bone marrow. EMH has been reported, albeit rarely, in pyogenic granuloma (PG), a polypoid lobular capillary hemangioma. However, statistical data have hitherto been lacking on the actual incidence of EMH in PG. Therefore, we here reviewed 157 consecutive cases using routine diagnostic surgical slides and found unequivocal EMH in 17 (10.8%). This indicates that EMH is a rather common finding in PG, which could thus have strong potential to be an important resource for the study of HSC.

e15128 Background: Excision repair cross-complementation group 1 gene (ERCC1) encodes an enzyme, which is essential for the effective repair of DNA damage induced by alkylating agents. Mitomycin-ba...

Extraskeletal myxoid chondrosarcoma and breast sarcomas are rare tumors accounting for less than 3% of all soft tissue sarcoma and less than 1% of all malignant breast tumors. We report a case of aggressive histologic features of myxoid chondrosarcoma in breast. A 50-year-old female presented with a well-defined mass at left breast. Histological features reveal stromal cells proliferation with abundance epithelioid cells with high mitotic activity in variably sized nodular architectures in myxoid matrix. Immuno-histochemical studies show strongly positive for S-100 protein, scattered positive for EMA and focal immunoreactivity for cyto-keratins. CD 34 and Bcl-2 were negative, leading us to diagnose high-grade extraskeletal myxoid chondrosarcoma. High-grade extraskeletal myxoid chondrosarcoma is a rare primary tumor in breast which resembles malignant cystosarcoma phyllodes and metaplastic carcinoma.

Tumor-infiltrating lymphocytes (TILs) are considered to be a manifestation of the host anti-tumor response. We aim to evaluate the prognostic significance of the immunophenotype, density and distribution of TILs in breast cancer samples. This was a retrospective study, using paraffin-embedded samples obtained from 43 breast cancer patients, treated at Mahasarakham Hospital between 2012 and 2013. TILs and prognostic markers were evaluated by immunohistochemical staining of tissue microarray cores, employing monoclonal antibodies to lymphocyte markers (i.e., CD3, CD4, CD8 and CD20) and markers for breast cancer (i.e., ER, PR, HER2 and Ki-67). TILs were categorized into: 1) intratumoral lymphocytes (ITLs) when found within tumor cell nests), and 2) peritumoral lymphocytes (PTLs) when infiltrating into the stroma, adjacent to the invasive front of tumor. Results A positive correlation was found between high density CD8+ PTLs and breast carcinoma without lymph node metastasis ( p = 0.044), and an inverse correlation was found between the density of CD4+ PTLs and estrogen receptor expression ( p = 0.027). The density of CD8+ PTLs as well as the number of CD20+ ITLs were independently, positively correlated with tumor size.

Kimura disease is a rare chronic inflammatory disorder of unknown etiology, characterized as painless subcutaneous mass which is rarely found outside head and neck region. We report an unusual presentation of Kimura disease of a 50-year-old man who presented with a progressive large non-tenderness right elbow mass for one year. Physical examination revealed a 10 cm soft tissue mass at the medial side of his right elbow. The Laboratory investigation showed peripheral eosinophilia. The clinical diagnosis was a soft tissue tumor. It also included the differential diagnosis of a parasitic infection. Surgical excision had been performed and the histology demonstrated a nodular lymphoid hyperplasia with prominent germinal centers, a large infiltration of eosinophils with a foci of eosinophilic micro-abscess and vascular proliferation which compatible with Kimura disease. Following surgery the patient visited again with the following symptoms, a left post auricular mass with multiple cervical lymph node enlargements. The excisional biopsy revealed the same histology as the elbow.

Pituitary adenomas are benign, slow-growing tumors of the pituitary gland that are most successfully treated with surgical removal. However, pituitary adenoma recurrence after surgery can occur. We aim to evaluate the clinical and pathological predictors of recurrent pituitary adenomas. Here we review 160 cases of pituitary adenomas operated 2009–2013. We found 20 patients who presented with tumor recurrence and a second operation had been undertaken. The clinicopathological data of these cases were reviewed.