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

Periwound Challenges Improve Patient Satisfaction in Wound Care

Summary:. In wound care, we usually focus nearly all of our efforts on the wound area while paying little attention to the periwound area. Although the periwound area may seem unimportant, it matters to patients. A female patient was admitted with a wound at the perianal area. Wound dressing was performed using standard wet-to-dry gauzes. The patient had several small complaints including irritant contact dermatitis, skin maceration, pain during dressing change, and fecal contamination to the wound. In this case, we ended up switching to a different method of wound dressing. We went from using wet-to-dry gauzes for the primary dressing to a hydrofiber with silver dressing and from gauze and Micropore as a secondary dressing to an adhesive sodium carboxymethylcellulose foam dressing. This resolved all complaints. The patient’s satisfaction score using visual analog scale increased from 2 to 10 (out of 10 points). This example shows how even small details can make a significant difference in wound care. Because periwound care is often neglected, therapeutic algorithm that integrates major challenges in periwound care into wound healing strategies is proposed

Radiographic features predictive of recurrence and survival after surgical resection of perihilar cholangiocarcinoma

Objective: To study which radiographic features were associated with recurrence and adverse outcome in patients undergoing surgical resection of perihilar cholangiocarcinoma (PCCA), as well as to evaluate the imaging patterns that signify recurrence after the resection of PCCA. Materials and methods: This study was conducted in a solitary tertiary center and utilized a retrospective, analytical, case-control design. The study population consisted of patients with pathologically confirmed PCCA who underwent surgical resection and were subsequently followed up from January 2009 to December 2017. A total of 77 patients were enrolled in the study and were categorized into two distinct groups, namely recurrent and non-recurrent. The analysis encompassed the examination of demographic data and recurrence patterns. Additionally, survival and multivariate analyses were employed to assess radiographic imaging data and surgical information. Results: Seventy-seven patients diagnosed with PCCA based on pathological evidence were included in the study. Among the participants, there were 28 females and 49 males, with ages ranging from 41 to 81 years (mean age of 60.65 ± 7.66). A noteworthy finding was the recurrence rate of 65 % observed following surgical resection. The presence of regional lymph node (LN) metastasis, adjacent organ invasion, and surgical margin emerged as the three independent factors that exhibited a significant association with recurrence after post-operative resection (p = 0.023, p = 0.028, and p = 0.010, respectively). The patients with PCCA who experienced regional LN metastasis had a median overall survival (OS) of 22 months, which was significantly lower than the 46 months observed in those without regional LN metastasis (p < 0.018). Furthermore, the individuals with regional LN metastasis had a death rate that was 2.08 times higher than those without (p = 0.040). In addition, those with adjacent organ invasion had an OS duration of 21 months compared with 52 months in those without (p = 0.008), and the rate of death was 2.39 times higher (p = 0.018). Patients with an R1 resection margin had an OS duration of 36 months compared with 51.56 months in those with an R0 resection margin (p = 0.006), as well as a 2.13 times higher rate of recurrence (p = 0.010) and a 2.43 times higher mortality rate (p = 0.013). Conclusion: The presence of regional LN metastasis, invasion of adjacent organs, and R1 resection margin were identified as distinct factors that are linked to both disease recurrence and reduced OS. Local recurrence, as well as the spread of cancer to distant organs such as the lungs and liver, were frequently observed patterns of recurrence. To enhance the precision of staging, prognosis, and treatment, the inclusion of periductal fat or invasion of adjacent organs should be considered in the staging system for PCCA

Chemotherapeutic resistant cholangiocarcinoma displayed distinct intratumoral microbial composition and metabolic profiles

Background Cholangiocarcinoma (CCA) is a malignancy of the cholangiocytes. One of the major issues regarding treatment for CCA patients is the development of chemotherapeutic resistance. Recently, the association of intratumoral bacteria with chemotherapeutic response has been reported in many cancer types. Method In the present study, we aimed to investigate the association between the intratumoral microbiome and its function on gemcitabine and cisplatin response in CCA tissues using 16S rRNA sequencing and 1H NMR spectroscopic analysis. Result The results of 16S rRNA sequencing demonstrated that Gammaproteobacteria were significantly higher in both gemcitabine- and cisplatin-resistance groups compared to sensitive groups. In addition, intratumoral microbial diversity and abundance were significantly different compared between gemcitabine-resistant and sensitive groups. Furthermore, the metabolic phenotype of the low dose gemcitabine-resistant group significantly differed from that of low dose gemcitabine-sensitive group. Increased levels of acetylcholine, adenine, carnitine and inosine were observed in the low dose gemcitabine-resistant group, while the levels of acetylcholine, alpha-D-glucose and carnitine increased in the low dose cisplatin-resistant group. We further performed the intergrative microbiome-metabolome analysis and revealed a correlation between the intratumoral bacterial and metabolic profiles which reflect the chemotherapeutics resistance pattern in CCA patients. Conclusion Our results demonstrated insights into the disruption of the microbiome and metabolome in the progression of chemotherapeutic resistance. The altered microbiome-metabolome fingerprints could be used as predictive markers for drug responses potentially resulting in the development of an appropriate chemotherapeutic drug treatment plan for individual CCA patients

In vitro and molecular chemosensitivity in human cholangiocarcinoma tissues.

Adjuvant chemotherapy is required for cholangiocarcinoma (CCA) patients after surgical treatment. Gemcitabine and gemcitabine plus cisplatin are considered the appropriate regimen; however, the response spectrum to chemotherapy differs between patients. Thus, the present study aims to evaluate the response pattern of individual CCA patients by using an in vitro method, histoculture drug response assay (HDRA), to predict the chemosensitivity of individual patients in a prospective study. Moreover, we also investigate the expression of gemcitabine and cisplatin sensitivity factors in CCA tissues in the same cases. Based on the dose response curve, 1000 and 1500 μg/ml of gemcitabine were used as the testing concentrations. For cisplatin, concentrations of 20 and 25 μg/ml were selected for testing and for the combination regimen, 1000 μg/ml of gemcitabine and 20 μg/ml of cisplatin were chosen. The median %IR of each drug was measured as the cut-off to categorize the response pattern into response and non-response groups. In addition, we compared the effectiveness of the chemotherapy regimens between gemcitabine alone and gemcitabine plus cisplatin. The %IR of the combination of gemcitabine and cisplatin was significantly higher than gemcitabine alone. The relationship between the expression level of gemcitabine and cisplatin sensitive factors and the individual response pattern as well as clinicopathological data of CCA patients were analyzed. The results indicated that a low expression of the gemcitabine sensitive factor hENT-1 was significantly associated with the non-response group in vitro (p = 0.002). Moreover, the low expression of hENT-1 was also significantly associated with advanced stages CCA in the patients (p = 0.025). A low expression of MT and ERCC1 was significantly correlated with the response group in the in vitro experiments (p = 0.015 and p = 0.037 for MT and ERCC1, respectively). Therefore, HDRA may serve as an aid to selecting chemotherapy, and the expression of hNET-1, MT and ERCC1 may serve as biomarkers for predicting chemotherapy success

Metabolomic analyses uncover an inhibitory effect of niclosamide on mitochondrial membrane potential in cholangiocarcinoma cells

Background Niclosamide is an oral anthelminthic drug that has been used for treating tapeworm infections. Its mechanism involves the disturbance of mitochondrial membrane potential that in turn inhibits oxidative phosphorylation leading to ATP depletion. To date, niclosamide has been validated as the potent anti-cancer agent against several cancers. However, the molecular mechanisms underlying the effects of niclosamide on the liver fluke Opisthorchis viverrini (Ov)-associated cholangiocarcinoma (CCA) cell functions remain to be elucidated. The aims of this study were to investigate the effects of niclosamide on CCA cell proliferation and on metabolic phenoconversion through the alteration of metabolites associated with mitochondrial function in CCA cell lines. Materials and Methods The inhibitory effect of niclosamide on CCA cells was determined using SRB assay. A mitochondrial membrane potential using tetramethylrhodamine, ethyl ester-mitochondrial membrane potential (TMRE-MMP) assay was conducted. Liquid chromatography-mass spectrometry-based metabolomics was employed to investigate the global metabolic changes upon niclosamide treatment. ATP levels were measured using CellTiter-Glo® luminescent cell viability assay. NAD metabolism was examined by the NAD+/NADH ratio. Results Niclosamide strongly inhibited CCA cell growth and reduced the MMP of CCA cells. An orthogonal partial-least square regression analysis revealed that the effects of niclosamide on suppressing cell viability and MMP of CCA cells were significantly associated with an increase in niacinamide, a precursor in NAD synthesis that may disrupt the electron transport system leading to suppression of NAD+/NADH ratio and ATP depletion. Conclusion Our findings unravel the mode of action of niclosamide in the energy depletion that could potentially serve as the promising therapeutic strategy for CCA treatment

Current Perspectives on Opisthorchiasis Control and Cholangiocarcinoma Detection in Southeast Asia

Similar to bile duct cancer or cholangiocarcinoma (CCA) in the western world, opisthorchiasis-associated CCA in Southeast Asia is an aggressive cancer with high mortality rates. It is known to cause a significant health burden in the opisthorchiasis region in Thailand and possibly throughout mainland Southeast. To reduce this health burden, a comprehensive prevention and control program for opisthorchiasis, as well as CCA, is required. In this review, our aim is to provide a brief update of the current situation regarding the natural history of opisthorchiasis and health burden of CCA in Southeast Asia. A comprehensive approach to tackling these issues being implemented in Thailand under the “Cholangiocarcinoma Screening and Care Program” is described. This comprehensive program consists of a three stage prevention and patient care program. The primary prevention component involves opisthorchiasis screening using a new and sensitive urine assay. The secondary prevention component involves screening for CCA and periductal fibrosis, with suspected CCA patients following the protocol for confirmation and appropriate treatment. Due to the eco-epidemiology of opisthorchiasis-induced CCA, the anticipated impacts and outcomes of the program include short-, medium-, and the long-term goals for the reduction of CCA incidence. To achieve long-term sustainable impacts, concerted efforts to raise social awareness and participating action by general public, non-government organizations, and government agencies are necessary. The strategic plans developed for this program can be expanded for use in other endemic areas as well as being a model for use in other chronic diseases

CD44 modulates metabolic pathways and altered ROS-mediated Akt signal promoting cholangiocarcinoma progression.

CD44 is a transmembrane glycoprotein, the phosphorylation of which can directly trigger intracellular signaling, particularly Akt protein, for supporting cell growth, motility and invasion. This study examined the role of CD44 on the progression of Cholangiocarcinoma (CCA) using metabolic profiling to investigate the molecular mechanisms involved in the Akt signaling pathway. Our results show that the silencing of CD44 decreases Akt and mTOR phosphorylation resulting in p21 and Bax accumulation and Bcl-2 suppression that reduces cell proliferation. Moreover, an inhibition of cell migration and invasion regulated by CD44. Similarly, the silencing of CD44 showed an alteration in the epithelial-mesenchymal transition (EMT), e.g. an upregulation of E-cadherin and a downregulation of vimentin, and the reduction of the matrix metalloproteinase (MMP)-9 signal. Interestingly, a depletion of CD44 leads to metabolic pathway changes resulting in redox status modification and Trolox (anti-oxidant) led to the recovery of the cancer cell functions. Based on our findings, the regulation of CCA progression and metastasis via the redox status-related Akt signaling pathway depends on the alteration of metabolic profiling synchronized by CD44