Mismatch Repair Deficiency Is a Prognostic Factor Predicting Good Survival of Opisthorchis viverrini-Associated Cholangiocarcinoma at Early Cancer Stage.

BACKGROUND: The mismatch repair (MMR) system prevents DNA mutation; therefore, deficient MMR protein (dMMR) expression causes genetic alterations and microsatellite instability (MSI). dMMR is correlated with a good outcome and treatment response in various cancers; however, the situation remains ambiguous in cholangiocarcinoma (CCA). This study aims to evaluate the prevalence of dMMR and investigate the correlation with clinicopathological features and the survival of CCA patients after resection. MATERIALS AND METHODS: Serum and tissues were collected from CCA patients who underwent resection from January 2005 to December 2017. Serum OV IgG was examined using ELISA. The expression of MMR proteins MLH1, MSH2, MSH6 and PMS2 was investigated by immunohistochemistry; subsequently, MMR assessment was evaluated as either proficient or as deficient by pathologists. The clinicopathological features and MMR status were compared using the Chi-square test. Univariate and multivariate analyses were conducted to identify prognostic factors. RESULTS: Among the 102 CCA patients, dMMR was detected in 22.5%. Survival analysis revealed that dMMR patients had better survival than pMMR (HR = 0.50, p = 0.008). In multivariate analysis, dMMR was an independent factor for a good prognosis in CCA patients (HR = 0.58, p = 0.041), especially at an early stage (HR = 0.18, p = 0.027). Moreover, subgroup analysis showed dMMR patients who received adjuvant chemotherapy had better survival than surgery alone (HR = 0.28, p = 0.012). CONCLUSION: This study showed a high prevalence of dMMR in cholangiocarcinoma with dMMR being the independent prognostic factor for good survival, especially in early-stage CCA and for patients who received adjuvant chemotherapy. dMMR should be the marker for selecting patients to receive a specific adjuvant treatment after resection for CCA.

Pathology of Cholangiocarcinoma.

The liver excretes bile through the biliary system, which has a complicated anatomical structure. Cholangiocarcinoma, a malignant bile duct epithelial tumor, is separated into intrahepatic and extrahepatic portions depending on the structure of the bile duct and exhibits both similarities and varieties in patient presentations and staging. The three main macroscopic characteristics of cholangiocarcinoma-mass formating, intraductal growth, and periductal infiltrating types-allow pathologists and surgeons to see and analyze the cancerous tissue. The majority of cholangiocarcinoma patients are in advanced stages and poor prognosis. Although surgery is the main treatment option, target therapy based on molecular pathology background offers hope for improving patient's prognosis.

Upgrade Rate and Predictive Factors Associated With Breast Papillary Lesions on Core Biopsy: A Canadian Experience.

Background: Papillary lesions of the breast are a heterogeneous group, encompassing a wide range of lesions. The histologic distinction between papillary breast lesions remains challenging, especially on core biopsy specimens. Aim: This study aimed to determine the rate of upgrade to atypia or malignancy of biopsy-proven papillary lesions on surgical follow-up and to assess for factors associated with an upgrade in Greater Vancouver, BC, Canada. Materials and Methods: This is a retrospective population-based study of all breast papillary lesions diagnosed on core biopsy between 2017 and 2019 in the Fraser Health Authority in Greater Vancouver, Canada. Patients were retrieved from the laboratory information system. Patient demographics, histopathologic, and radiologic findings were analyzed. Results: A total of 269 specimens from 269 patients (mean 61.1 years), including 265 female and 4 male patients, were included in the study. Of the 269 specimens, 129 (48%) were intraductal papillomas and 140 (52%) were atypical papillary lesions. The overall upgrade rate among papillomas was 11.6% (15 of 129) on final excision. The mean age of patients diagnosed with papilloma on core biopsy was significantly younger than those with atypical papillary lesions (55.6 vs 66.1 years, P < .0001). Lesion size in patients with papillomas on core biopsy was significantly smaller than those with atypical papillary lesions (11.1 vs 15.1 mm, P = .001). The upgrade rates in patients <55 and ≥55 years were 4.9% and 13.2%. Size (P = .004) and atypia on core biopsy (P = .009) were significantly associated with upgrade. Older age (>55 years) (OR = 5.3, 95% CI: 1.04-27.08) was an independent predictor of upgrade among papillomas. Size, location, and Breast Imaging-Reporting and Data System (BI-RADS) radiologic categories in our study were not associated with predicting the upgrade of papillomas. Conclusion: Our data suggest that the risk of upgrade to atypia or malignancy is sufficient to warrant the excision of benign papillomas of any size in patients aged ≥55 years. In patients younger than 55 years, observation with close clinical and radiological follow-up without surgery may be sufficient. Our findings also support surgical excision of papillomas diagnosed on core biopsy when associated with atypia.

Prognostic significance of tumor-infiltrating lymphocytes in predicting outcome of distal cholangiocarcinoma in Thailand.

Patients with distal cholangiocarcinoma (dCCA) generally have poor outcomes because of late presentation and diagnosis. Therefore, prognostic factors for predicting outcomes are essential to improve therapeutic strategies and quality of life. Tumor-infiltrating lymphocytes (TILs) have been reported as a prognostic predictor in several cancers. However, their role in dCCA is still unclear. This study aimed to evaluate the association of TILs with outcome in patients with dCCA. Fifty-two patients were evaluated for the percentage rate of TILs in their cancers, and a median TIL level was used to divide the patients into two groups. Survival, multivariate, and correlation analyses were performed to determine the prognostic factors. Results showed that a low TIL level was associated with poor survival. Multivariate analysis revealed TILs as an independent factor for poor outcome. Moreover, TILs were markedly correlated with growth patterns, and both were applied to classify patients with dCCA. Subgroups of TILs with growth pattern incorporation improved stratification performance in separating good from poor patient outcomes. This study suggested that TILs could be a prognostic factor for predicting survival and for clustering patients with dCCA to improve prognostication capability. This finding may be incorporated into a new staging system for stratifying dCCA in Thailand.

Modification of the eighth AJCC/UICC staging system for perihilar cholangiocarcinoma: An alternative pathological staging system from cholangiocarcinoma-prevalent Northeast Thailand.

Aim: This study aims to improve the classification performance of the eighth American Joint Committee on Cancer (AJCC) staging system for perihilar cholangiocarcinoma (pCCA) by proposing the Khon Kaen University (KKU) staging system developed in cholangiocarcinoma-prevalent Northeast Thailand. Method: Four hundred eighty-eight patients with pCCA who underwent partial hepatectomy between 2002 and 2017 at the Srinagarind Hospital, Faculty of Medicine, Khon Kaen University, Thailand, were included. Overall survival (OS) related to clinicopathological features was analyzed using the Kaplan-Meier method. Logrank test was performed in univariate analysis to compare OS data of clinicopathological features to determine risk factors for poor survival. Significant features were further analyzed by multivariate analysis (Cox regression) to identify prognostic factors which were then employed to modify the eighth AJCC staging system. Results: Multivariate analysis showed that growth pattern (HR = 4.67-19.72, p < 0.001), moderately and poorly differentiated histological grades (HR = 2.31-4.99, p < 0.05 and 0.001, respectively), lymph node metastasis N1 and N2 (HR = 1.37 and 2.18, p < 0.05 and 0.01, respectively), and distant metastasis (HR = 2.11, p < 0.001) were independent factors when compared to their respective reference groups. There was a clear separation of patients with pCCA into KKU stage: I [OS = 116 months (mo.)], II (OS = 46 mo.), IIIA (OS = 24 mo.), IIIB (11 mo.), IVA (OS = 7 mo.), and IVB (OS = 6 mo.). Conclusion: The new staging system was based on the incorporation of growth patterns to modify the eighth AJCC staging system. The classification performance demonstrated that the KKU staging system was able to classify and distinctly separate patients with pCCA into those with good and poor outcomes. It was also able to improve the stratification performance and discriminative ability of different stages of pCCA classification better than the eighth AJCC staging system. Hence, the KKU staging system is proposed as an alternative model to augment the accuracy of survival prognostication and treatment performance for patients with pCCA.

Modification of the AJCC/UICC 8th edition staging system for intrahepatic cholangiocarcinoma: proposal for an alternative staging system from cholangiocarcinoma-prevalent Northeast Thailand.

BACKGROUND: Intrahepatic cholangiocarcinoma (iCCA) arises from bile ducts within the liver. Thailand has the highest incidence of CCA worldwide, with a high mortality rate. Early diagnosis and accurate prognostic stratification can improve overall survival. We aim to modify the AJCC/UICC 8th edition staging system for iCCA by creating the Khon Kaen University (KKU) staging system for more precise patient stratification and prognostic prediction. METHODS: A total of 298 iCCA patients who underwent hepatectomy were included in this retrospective study at the Srinagarind Hospital, Khon Kaen University, Thailand. Univariate and multivariate analysis were performed to examine survival rate, hazard ratio, and prognostic factors. RESULTS: Univariate and multivariate analysis of the cohort showed that growth patterns, histological type, histological grade, lymph node metastasis and distant metastasis were independent prognostic factors when compared to the respective reference groups. The 8th AJCC staging system incorporated growth patterns into the KKU staging system. This model modified AJCC stages I, II, and III for better prediction of patient survival. CONCLUSION: Growth patterns were incorporated to improve the 8th AJCC staging system for prognostication of iCCA patients in Northeast Thailand. We propose the KKU staging system as an alternative model for iCCA staging to augment the accuracy of survival prognostication.

The Impact of Pre-analytical Quality Initiatives on Cholangiocarcinoma Diagnostics in Thailand.

Cholangiocarcinoma (CCA) is the most prevalent malignancy in Thailand, with unfortunate late diagnosis and frequent metastatic disease outcomes. An accurate tissue diagnosis is the first and most important step in the treatment of CCA. Tissue quality and preservation during the pre-analytical phase play major roles in the proper histological evaluation and potential biomarker testing. This study evaluated the impact of using the "Cholangiocarcinoma Screening and Care Program (CASCAP)" container, as an innovative tool to address pre-analytical challenges faced by pathology laboratories in Thailand. This is a comparison study examining the quality of CCA specimens using the CASCAP container vs. the conventional method, using hematoxylin and eosin (H&E) and immunohistochemistry (IHC). CCA tissue quality using the CASCAP container significantly reduced artifact deposition while improving the cellular structure and nuclear and cytoplasmic morphologies. The immunohistochemical expression of cytokeratin 19 (CK19), a prognostic marker in CCA, significantly improved in the CASCAP container group in comparison with the conventional method. This innovation is proven to significantly enhance the CCA tissue quality diagnostics and prognostic biomarker testing, hence improving overall cancer care, diagnosis, and treatment in Thailand.

Prognostic Significance of Growth Pattern in Predicting Outcome of Opisthorchis viverrini-Associated Distal Cholangiocarcinoma in Thailand.

Distal cholangiocarcinoma (dCCA) is a rare type of CCA in Asia, even in Opisthorchis viverrini-prevalent Northeastern Thailand. The clinical ambiguity and imprecision of diagnosis surrounding this malignancy result in high mortality due often to advanced/metastatic disease on presentation. We aim to identify a prognostic factor that can improve the performance stratification and influence the outcome of dCCA patients after curative resection. A total of 79 patients who underwent curative-intended surgery for dCCA was enrolled. Possible risk factors for survival were analyzed with log-rank test, and independent factors with Cox regression model. dCCA patients were staged and classified according to the 8th edition the American Joint Committee on Cancer (AJCC) Staging Manual. Results were then compared with the revised classification employing the prognostic factor identified from multivariate analysis. Multivariate analysis revealed that growth pattern (p < 0.01) and distant metastasis (p = 0.012) were independent factors. Growth patterns comprise intraductal (ID), periductal infiltrating (PI), mass-forming (MF), and mixed types. When dCCA patients were grouped into those having good and poor outcomes (with and without ID components, respectively). The survival outcomes significantly differed among patients with and without ID components, which was better than with the 8th AJCC staging system in our cohort. Furthermore, Chi-square test showed that patterns without ID components (PI, MF, PI + MF) correlated with lymph node and distant metastasis. Therefore, classification of dCCA patients after curative-intended surgical resection based on growth pattern provides additional beneficial information for the prediction of survival in dCCA patients.

Pathum Raksa Project: Addressing Disparity in Breast Cancer Care Through National Innovation in Thailand.

PURPOSE: Breast cancer is a growing public health challenge in Thailand. Pathum Raksa project was launched in 2015, as a result of higher than expected rate of triple-negative breast cancers in Thai women. The purpose of this project was to identify the cause(s) and address the issue(s), hence improving the quality of breast cancer biomarker testing in Thailand. MATERIALS AND METHODS: Nineteen hospitals across the country, with 902 breast cancer patients were enrolled in this study during 2015-2020. The pre- and post-data from Pathum Raksa initiative was only available for Khon Kaen University (KKU) and Udonthani hospitals in Northeast Thailand. We developed a resource-stratified strategic plan that included designing a unique specimen container, forming multidisciplinary teams from the Surgery and Pathology Departments, and employing locally developed innovative technologies to optimize the entire process of breast cancer diagnostics and biomarker testing. RESULTS: The rate of triple-negative breast cancers in KKU and Udonthani decreased 52.8% (p = 0.02) and 28.9% (p = 0.48), respectively. The rate of ER+ breast cancers in both hospitals increased 5% post-Pathum Raksa implementation. The rate of HER2-neu+ (score 3+) also increased in both hospitals (particularly an increased 65% rate in KKU). Luminal A/B cancers were the most common subtype in both KKU and Udonthani hospitals. CONCLUSION: Pathum Raksa project has significantly improved breast cancer biomarker testing in Thailand. As a result of this national innovation, false-negative rates of breast biomarkers have significantly decreased, resulting in improving prognosis, treatment, and survival of breast cancer women in Thailand.

Targeting Fatty Acid Synthase Modulates Metabolic Pathways and Inhibits Cholangiocarcinoma Cell Progression.

An aberrant regulation of lipid metabolism is involved in the pathogenesis and progression of cancer. Up-regulation of lipid biosynthesis enzymes, including acetyl-CoA carboxylase (ACC), fatty acid synthase (FASN) and HMG-CoA reductase (HMGCR), has been reported in many cancers. Therefore, elucidating lipid metabolism changes in cancer is essential for the development of novel therapeutic targets for various human cancers. The current study aimed to identify the abnormal expression of lipid-metabolizing enzymes in cholangiocarcinoma (CCA) and to evaluate whether they can be used as the targets for CCA treatment. Our study demonstrated that a high expression of FASN was significantly correlated with the advanced stage in CCA patients. In addition, survival analysis showed that high expression of FASN and HMGCR was correlated with shorter survival of CCA patients. Furthermore, FASN knockdown inhibited the growth, migration and invasion in CCA cell lines, KKU055 and KKU213, as well as induced cell cycle arrest and apoptosis in the CCA cell lines. In addition, metabolomics study further revealed that purine metabolism was the most relevant pathway involved in FASN knockdown. Adenosine diphosphate (ADP), glutamine and guanine levels significantly increased in KKU213 cells while guanine and xanthine levels remarkably increased in KKU055 cells showing a marked difference between the control and FASN knockdown groups. These findings provide new insights into the mechanisms associated with FASN knockdown in CCA cell lines and suggest that targeting FASN may serve as a novel CCA therapeutic strategy.

Pathological practice and management of thyroid nodules: a Thai perspective.

Although, in the thyroid field, there have been several internationally standard diagnostic and management guidelines for practitioners from every country to follow but there is still variation among physicians across the globe in taking care of patients and pathology specimens with thyroid nodules due to dissimilar backgrounds of each place. Thailand is one among several countries that tries to maintain standard of care to meet international requirements although, with some limitations, not all recommendations are followed. To understand how approaches of thyroid nodules are performed throughout the country and how the healthcare system of the whole kingdom is managed including what major current limitations, the authors conducted a survey among physicians consisting of surgeons, radiologists and pathologists who are involved in the management of the thyroid lesions by personal phone contact and custom online questionnaires. Performances of fine needle aspiration of different institutes are also evaluated by analyzing the data from available publications and compared their results with other series from the literature. Shortage of pathologists and un-equal resource allocation are the major problems concerning administrative aspect while a lack of awareness in new terminologies or diagnostic systems (e.g., NIFTP, UMP, Bethesda, TI-RADS) among physicians, particularly clinicians, are the problems of training and continuous medical education. Another point of concern is a rather poor performance in fine needle aspiration from the Thai series in which there are high rate (30.5%) of non-diagnostic category (Bethesda I) and false negativity as demonstrated by relatively high risk of malignancy (9.6%) in Bethesda II compared with other series from the literature. Regarding molecular studies, despite their usefulness in improving diagnostic accuracy, especially for cytology specimens, these ancillary tools are not routinely used in our practice since they are available in only few referral centers. This review provided a background information of the perspective on how thyroid nodules are managed in the Thai settings.

Human Papillomavirus Detection and Abnormal Anal Cytology in HIV-infected Patients Using p16/Ki-67 Dual-Staining.

OBJECTIVE: We investigated human papillomavirus (HPV) infection and detected anal squamous intraepithelial lesions by modified liquid-based cytology (LBC) and p16/Ki67 dual-staining. METHODS: Anal swabs (n=393) were collected from patients with HIV infection. Anal cells were kept in 95% ethyl alcohol for modified LBC. DNA was extracted from cells for HPV detection and genotyping using real-time PCR and reverse line blot hybridization. RESULTS: Nine samples (2.3%) were unsatisfactory specimens, 74.8% (294/393) were negative for intraepithelial malignancies (NILM) and 22.9% (90/393) exhibited squamous intraepithelial lesions (SIL). In the latter category, 13.7% of samples (54/393) contained atypical squamous cells of undetermined significance (ASCUS), 6.9% (27/393) were classified as low-grade SIL (LSIL) and 2.3% (9/393) as high-grade SIL (HSIL). A total of 331 from 393 swab samples were suitable for detection of HPV infection. Among these, 34.1% (113/331) were positive. HPV 58 (15.9%) was the most common genotype, followed by HPV 18 (14.2%) and HPV 16 (11.5%). The severity of abnormal cells was significantly associated with HPV infection. Dual staining with p16/Ki-67 was performed on 130 samples: in 30.8% (40/130) of samples positive staining was significantly associated with severity of abnormal cells. Agreement between cytology, p16/Ki67 dual-staining and high-risk HPV detection was 100% in HSIL samples. Interestingly, eight apparently NIML cases might have contained abnormal cells, since they were positive by both p16/Ki67 dual-staining and high-risk HPV detection. CONCLUSION: Anal specimens screened using modified LBC with 95% ethyl alcohol solution as the fixative are suitable for screening anal precancerous lesions by cytology, HPV testing and p16/Ki-67 dual staining.

A comparison of the proportion of early stage cholangiocarcinoma found in an ultrasound-screening program compared to walk-in patients.

BACKGROUND: Patients with cholangiocarcinoma (CCA) usually have no specific symptoms until an advance stage of the disease and curative treatment is not possible. Patients with early stage, operable disease can be found using ultrasonography (US). A US-screening program was implemented in Thailand where CCA incidence is the highest worldwide. Here we evaluate the effectiveness of the program by comparing the proportion of individuals with early stage CCA in the screening group with that of the walk-in group presenting at hospitals with clinical symptoms. METHODS: All patients had a pathological diagnosis of CCA. The difference in the proportions and the 95% confidence interval (CI) were obtained using binomial regression. RESULTS: Of the 762 histologically proven CCA cases, 161 were from the screening group and 601 from the walk-in group. The proportion of early stage CCA (stages 0 to II) diagnosed was 84.5% in the screening and 21.6% in the walk-in groups. After adjustment age, gender, and liver fluke infection, there was a significantly higher proportion (P < 0.001) and higher chance (P < 0.001) of having early stage CCA in the screening group than in the walk-in group. CONCLUSIONS: US-screening is an effective tool for detecting early stage, operable CCA in high incidence areas.

Breast Cancer Incidence Trends and Projections in Northeastern Thailand.

BACKGROUND: The northeast has the lowest incidence of breast cancer of all regions in Thailand, although national rates are increasing. The heterogeneity in subnational trends necessitates a comprehensive evaluation of breast cancer incidence trends and projections to provide evidence for future region-specific strategies that may be employed to attenuate this growing burden. METHODS: Joinpoint regression and age-period-cohort modeling were used to describe trends from 1988-2012. Data was projected from three separate models to provide a range of estimates of incidence to the year 2030 by age group. RESULTS: Age-standardized rates (ASRs) increased significantly for all women from 1995-2012 by 4.5% per year. Rates for women below age 50 increased by 5.1% per year, while women age 50 years and older increased by 6% per year from 1988-2012. Projected rates show that women age 50 years and older have the largest projected increase in ASRs by 2030 compared to younger women and all women combined. CONCLUSIONS: Breast cancer trends in Khon Kaen are presently lower than other regions but are expected to increase and become comparable to other regions by 2030, particularly for women ages 50 years and older.

Current Status of Thyroid Fine-Needle Aspiration Practice in Thailand.

Thyroid carcinoma is one of the leading malignancies in Thailand increasingly prevalent in the female population. Fine-needle aspiration (FNA) cytology is a widely used diagnostic tool for evaluation of thyroid nodules and thyroid cancer. Thyroid FNA is a routine procedure universally performed in Thai hospitals by a variety of clinical specialists. Manual guidance is the first-line choice complemented by ultrasound assistance in selected cases. Despite national guidelines recommendations, the diagnostic criteria and terminology of the Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) was slowly adopted in the local settings. Currently, the Bethesda system is actively promoted by the local professional societies as a uniform reporting system. Experience with thyroid FNA has been rarely reported to date-only a handful of publications are available in local journals. Our review, in addition to presenting various aspects of thyroid FNA in Thailand, established for the first time national references for a certain statistical outputs of TBSRTC based on the original multi-institutional cohort. The risk of malignancy in 2,017 operated thyroid nodules collected from three tertiary thyroid cancer centers was 21.7%, 14.7%, 35.9%, 44.4%, 76.7%, and 92.6% for categories I to VI, respectively. The malignancy risk in several diagnostic categories (II to IV) was higher than the risk estimated by TBSRTC and recent meta-analysis studies. We endorse the use of uniform terminology of the Bethesda system in Thailand, which will help facilitate communication among diverse medical professionals involved in the management of patients with thyroid nodules, to share local experience with the international audience.

Evaluating a preoperative protocol that includes magnetic resonance imaging for lymph node metastasis in the Cholangiocarcinoma Screening and Care Program (CASCAP) in Thailand.

BACKGROUND: Treatment planning especially liver resection in cholangiocarcinoma (CCA) depends on the extension of tumor and lymph node metastasis which is included as a key criterion for operability. Magnetic resonance imaging (MRI) offers a rapid and powerful tool for the detection of lymph node metastasis (LNM) and in the current manuscript is assessed as a critical tool in the preoperative protocol for liver resection for treatment of CCA. However, the accuracy of MRI to detect LNM from CCA had yet to be comprehensively evaluated. METHODS: The accuracy of MRI to detect LNM was assessed in a cohort of individuals with CCA from the Cholangiocarcinoma Screening and Care Program (CASCAP), a screening program designed to reduce CCA in Northeastern Thailand by community-based ultrasound (US) for CCA. CCA-positive individuals are referred to one of the nine tertiary centers in the study to undergo a preoperative protocol that included enhanced imaging by MRI. Additionally, these individuals also underwent lymph node biopsies for histological confirmation of LNM (the "gold standard") to determine the accuracy of the MRI results. RESULTS: MRI accurately detected the presence or absence of LNM in only 29 out of the 51 CCA cases (56.9%, 95% CI 42.2-70.7), resulting in a sensitivity of 57.1% (95% CI 34.0-78.2) and specificity of 56.7% (95% CI 37.4-74.5), with positive and negative predictive values of 48.0% (95% CI 27.8-68.7) and 65.4% (95% CI 44.3-82.8), respectively. The positive likelihood ratio was 1.32 (95% CI 0.76-2.29), and the negative likelihood ratio was 0.76 (95% CI 0.42-1.36). CONCLUSIONS: MRI showed limited sensitivity and a poor positive predictive value for the diagnosis of LNM for CCA, which is of particular concern in this resource-limited setting, where simpler detection methods could be utilized that are more cost-effective in this region of Thailand. Therefore, the inclusion of MRI, a costly imaging method, should be reconsidered as part of protocol for treatment planning of CCA, given the number of false positives, especially as it is critical in determining the operability for CCA subjects.

False-Negative Rate of Papanicolaou Testing: A National Survey from the Thai Society of Cytology.

OBJECTIVE: To evaluate the performance of Papanicolaou smear screening in Thailand at the national level, and to propose recommendations for continuing quality control. STUDY DESIGN: This study was conducted by The Thai Society of Cytology and involved 124 laboratories in 76 provinces during 2010-2014. Random sampling suggested recalling of 10% of slides defined as negative at routine screenings (10% random rescreening [R10] model) directly from the reading unit. RESULTS: Out of 330,075 smears covered by the rescreening project throughout its 5-year duration, the rates of abnormal, unsatisfactory, and normal results were 0.63, 1.82, and 97.55%, respectively. Abnormal findings were largely represented by ASC-US (54%) and L-SIL (21%). The average false-negative rate (FNR) measured at the level of L-SIL and higher was 13.8%. CONCLUSION: The national project was developed to address the accuracy of cervical cancer screening and to promote internal quality assurance based on the R10, on-site surveys, and education. The major output parameters of this study (FNR and number and distribution of abnormal cases on rescreening) improved significantly in the main phase of the project (2012-2014), after revising substantial logistics issues encountered during the first 2 years of this study. This project provided objective measurable evidence related to the quality of cytology-based cervical cancer screening in Thailand.

Joinpoint Analysis Trends in the Incidence of Colorectal Cancer in Khon Kaen, Thailand (1989 ­ 2012)

Objective: This study focused on recent changes in the incidence of colorectal cancer (CRC) in Khon Kaen, Thailand. Methods: Data for CRC over the period 1989 to 2012 from the population-based cancer registry of Khon Kaen province were employed. Age-standardized incidence rates (ASR) were calculated and classified into 4 age-groups for comparison. Joinpoint regression analysis was used to detect changes in trends among each line segment and an overall line was generated, whether increasing or decreasing, with annual percent change (APC) and average annual percent change (AAPC). Results: There were 3,364 CRC cases included in the analysis, 72.2% histological confirmed and 53.5% in men. Trends of ASRs generally demonstrated gradual increase over the period 1989 to 2012. For those aged under 45 or 50 years there was slight overall increase, with a somewhat zigzag pattern. From joinpoint analysis, the trends of all aged groups were found to be increasing among both men and women: aged 45 years and older group AAPC=3.40, 2.30 and 3.90, respectively); aged 50 years and older group AAPC=2.90, 2.20 and 3.40; aged under 45 years AAPC=6.30, 6.00 and 6.90; and aged under 50 years (AAPC=5.70, 3.20 and 5.70. Conclusions: ASRs for CRC have been gradually increasing in the northeast region of Thailand. Future studies should consider the subsite distribution.

Urinary microRNA-192 and microRNA-21 as potential indicators for liver fluke-associated cholangiocarcinoma risk group.

Opisthorchis viverrini infection induces chronic inflammation in the bile ducts, leading to periductal fibrosis (PDF), which possibly associates to cholangiocarcinoma (CCA). Patients with CCA have a poor prognosis, which is linked to asymptomatic disease and late diagnosis. Hence, detecting early stage CCA is essential. Secretory miRNAs have been promoted as biomarkers for pathological changes associated with parasitic infections, fibrosis and/or cancer. We aimed to determine levels of miR-192 and miR-21 in the urine of O. viverrini infected, periductal fibrosis (PDF) and CCA groups using qRT-PCR. We found that miR-192 was significantly higher in O. viverrini infected, PDF and also CCA groups (p<0.05) than in healthy controls. By utilizing the Receiver Operation Characteristics (ROC) analysis, miR-192 differentiated patients with opisthorchiasis (the area under the curve; AUC=0.766), PDF subjects (AUC=0.781) and CCA patients (AUC=0.682) from healthy controls. MiR-21 was significantly higher in PDF and CCA groups (p<0.05) than in healthy controls. MiR-21 discriminated PDF subjects (AUC=0.735) and CCA patients (AUC=0.682) from healthy controls. Combined levels of these two miRNAs revealed an increased AUC of 0.812 for separating opisthorchiasis, AUC of 0.815 in discriminating PDF subjects, and AUC of 0.849 in differentiating CCA from healthy controls. Odds ratios (OR) indicated high levels of miR-192/miR-21 as risk predictors for opisthorchiasis, PDF and CCA. Levels of these miRNAs declined significantly for patients following praziquantel treatment. In conclusion, urinary miR-192/miR-21 have potential as risk indicators for opisthorchiasis and PDF-associated CCA in the endemic region.

Upregulation of endothelial nitric oxide synthase (eNOS) and its upstream regulators in Opisthorchis viverrini associated cholangiocarcinoma and its clinical significance.

Endothelial nitric oxide synthase (eNOS) is an isoform of the enzyme nitric oxide synthase (NOS) which is constitutively expressed in endothelial cells and plays important roles in vasodilation. We previously reported the importance of eNOS activation in cholangiocarcinoma (CCA) tissues and cell lines. The present study aims to investigate the relative abundance of eNOS and phosphorylated eNOS (P-eNOS) and their upstream regulators VEGFR3, VEGFC, EphA3 and ephrin-A1, in the Opisthorchis viverrini (Ov)/N-nitrosodimethylamine (NDMA)-induced hamster CCA model and in human CCA by semiquantitative immunohistochemical analysis of the relevant tissues. Results from the hamster model suggested an increase in eNOS and P-eNOS and upstream regulators during CCA genesis. In human CCA, high immunohistochemical staining intensity of all investigated proteins was associated with the presence of metastasis. A pairwise analysis of the staining data for eNOS and its upstream regulators showed that a concurrent increase in eNOS/VEGFR3, eNOS/ephrin-A1, eNOS/VEGFC and eNOS/EphA3 was significantly associated with metastasis. An increase in eNOS/VEGFR3, eNOS/ephrin-A1 was also associated with non-papillary type CCA. Additionally, an increase in eNOS and P-eNOS was significantly correlated with a high micro-vessel level (P=0.04). Our results indicate that the development of CCA involves upregulation of eNOS and P-eNOS and their regulators. This may drive angiogenesis and metastasis in CCA.