Chemotherapy of Cholangiocarcinoma: Current Management and Future Directions

Cholangiocarcinoma is a relatively rare form of gastroenterological cancer that divided into intrahepatic, perihilar, and distal bile duct cancer. Approximately, 10,000 new cases are diagnosed annually in the United States, and a 5-year survival rate is below 20%. While only surgical resection can provide a cure, most of cholangiocarcinomas are detected at inoperable stage and associated with poor prognosis. Moreover, cholangiocarcinoma has a high recurrence rate, even after curative surgery. Therefore, chemotherapy has an important role in the treatment of patients with cholangiocarcinoma. International efforts by physicians and researchers are revealing genetic factors of cholangiocarcinoma progression, which will identify early diagnostic markers and novel therapeutic targets. In this chapter, current strategies of adjuvant, neoadjuvant, and palliative chemotherapy will be discussed, as well as expectant future therapeutic targets and development of individualized therapies

Inter-rater agreement among shoulder surgeons on treatment options for proximal humeral fractures among shoulder surgeons

Background The treatment approach for proximal humeral fractures is determined by various factors, including patient age, sex, dominant arm, fracture pattern, presence of osteoporosis, preexisting arthritis, rotator cuff status, and medical comorbidities. However, there is a lack of consensus in the literature regarding the optimal treatment for displaced proximal humeral fractures. This study aimed to assess and quantify the decision-making process for either conservative or surgical treatment and the choice of surgical method among shoulder surgeons when treating proximal humeral fractures. Methods Forty sets of true anteroposterior view, scapular Y projection view, and three-dimensional computed tomography of proximal humeral fractures were provided to 12 shoulder surgeons along with clinical information. Surveys regarding Neer classification, decisions between conservative and surgical treatments, and chosen methods were conducted twice with an interval of 2 months. The factors affecting the treatment plans were also assessed. Results The inter-rater agreement was fair for Neer classification (kappa=0.395), moderate for the decision between conservative and surgical treatments (kappa=0.528), and substantial for the chosen method of surgical treatment (kappa=0.740). The percentage of agreement was 71.1% for Neer classification, 84.6% for the decision between conservative and surgical treatment, and 96.4% for the chosen method of surgical treatment. The fracture pattern was the most crucial factor in deciding between conservative and surgical treatments, followed by age and physical activity. Conclusions The decision between conservative and surgical treatment for proximal humeral fractures showed good agreement, while the chosen method between osteosynthesis and arthroplasty showed substantial agreement among shoulder surgeons

Effect of Epigallocatechin-3-Gallate on PMA-Induced MUC5B Expression in Human Airway Epithelial Cells

ObjectivesAmong the inflammatory mediators, phorbol 12-myristate 13-acetate (PMA) is associated with the regulation of MUC5B expression in the airway epithelial cells. Epigallocatechin-3-gallate (EGCG) is the major component of green tea extract. The biological activity of EGCG includes reduction of cholesterol and antioxidant activity, as well as anti-inflammatory effect. However, the precise action mechanism of anti-inflammatory effect of EGCG in the airway epithelial cells has not been fully defined. This study investigates the effect and the brief signaling pathway of EGCG on PMA-induced MUC5B expression in the airway epithelial cells.MethodsIn NCI-H292 airway epithelial cells, the effect and signaling pathway of EGCG on MUC5B expression were investigated using real-time polymerase chain reaction analysis, enzyme immunoassay, immunohistochemical analysis, gelatin zymography assay, and immunoblot analysis.ResultsIn NCI-H292 airway epithelial cells, PMA induced MUC5B expression, phosphorylation of p38 mitogen-activated protein kinase (MAPK), and matrix metalloproteinase-9 (MMP-9) expression and protein activity. EGCG significantly decreased PMA-induced MUC5B expression, phosphorylation of p38 MAPK, and MMP-9 expression and protein activity. SB203580 (p38 MAPK inhibitor) significantly decreased PMA-induced MMP-9 expression. In addition, SB203580 and MMP-9 I (MMP-9 inhibitor) significantly decreased PMA-induced MUC5B expression.ConclusionThese results suggest that EGCG down-regulates PMA-induced MUC5B expression through the p38 MAPK dependent MMP-9 signaling pathway in human airway epithelial cells

Identification of potential biomarkers for diagnosis of pancreatic and biliary tract cancers by sequencing of serum microRNAs

Background Pancreatic and biliary tract cancer (PC and BTC, respectively) are difficult to diagnose because of their clinical characteristics; however, recent studies suggest that serum microRNAs (miRNAs) might be the key to developing more efficient diagnostic methods for these cancers. Methods We analysed the genome-wide expression of serum miRNAs in PC and BTC patients to identify novel biomarker candidates using high-throughput sequencing and experimentally validated miRNAs on clinical samples. Results Statistical and classification analysis of the serum miRNA-expression profiles of 55 patient samples showed distinguishable patterns between cancer patients and healthy controls; however, we were unable to distinguish the two cancers. We found that three of the highest performing miRNAs were capable of distinguishing cancer patients from controls, with an accuracy of 92.7%. Additionally, dysregulation of these three cancer-specific miRNAs was demonstrated in an independent sample group by quantitative reverse transcription polymerase chain reaction. Conclusions These results suggested three candidate serum miRNAs (mir-744-5p, mir-409-3p, and mir-128-3p) as potential biomarkers for PC and BTC diagnosis.This work was supported by the Post-Genome Technology Development Program. (No. 10040174; Multiple biomarker development through validation of useful markers generated by next-generation bio-data-based genome research) funded by the Ministry of Trade, Industry, and Energy (MOTIE, Korea). The funders had no role in study design, data collection, analysis and interpretation of data, or in the writing of the manuscript

The T2-Shortening Effect of Gadolinium and the Optimal Conditions for Maximizing the CNR for Evaluating the Biliary System: a Phantom Study

OBJECTIVE: Clear depiction of the common bile duct is important when evaluating neonatal cholestasis in order to differentiate biliary atresia from other diseases. During MR cholangiopancreatography, the T2-shortening effect of gadolinium can increase the contrast-to-noise ratio (CNR) of the bile duct and enhance its depiction. The purpose of this study was to confirm, by performing a phantom study, the T2-shortening effect of gadolinium, to evaluate the effect of different gadolinium chelates with different gadolinium concentrations and different magnetic field strengths for investigating the optimal combination of these conditions, and for identifying the maximum CNR for the evaluation of the biliary system. MATERIALS AND METHODS: MR imaging using a T2-weighted single-shot fast spin echo sequence and T2 relaxometry was performed with a sponge phantom in a syringe tube. Two kinds of contrast agents (Gd-DTPA and Gd-EOB-DTPA) with different gadolinium concentrations were evaluated with 1.5T and 3T scanners. The signal intensities, the CNRs and the T2 relaxation time were analyzed. RESULTS: The signal intensities significantly decreased as the gadolinium concentrations increased (p < 0.001) with both contrast agents. These signal intensities were higher on a 3T (p < 0.001) scanner. The CNRs were higher on a 1.5T (p < 0.001) scanner and they showed no significant change with different gadolinium concentrations. The T2 relaxation time also showed a negative correlation with the gadolinium concentrations (p < 0.001) and the CNRs showed decrease more with Gd-EOB-DTPA (versus Gd-DTPA; p < 0.001) on a 3T scanner (versus 1.5T; p < 0.001). CONCLUSION: A T2-shortening effect of gadolinium exhibits a negative correlation with the gadolinium concentration for both the signal intensities and the T2 relaxation time. A higher CNR can be obtained with Gd-DTPA on a 1.5T MRI scannerope

Preclinical evaluation of injectable sirolimus formulated with polymeric nanoparticle for cancer therapy

Nanoparticles are useful delivery vehicles for promising drug candidates that face obstacles for clinical applicability. Sirolimus, an inhibitor of mammalian target of rapamycin has gained attention for targeted anticancer therapy, but its clinical application has been limited by its poor solubility. This study was designed to enhance the feasibility of sirolimus for human cancer treatment. Polymeric nanoparticle (PNP)–sirolimus was developed as an injectable formulation and has been characterized by transmission electron microscopy and dynamic light scattering. Pharmacokinetic analysis revealed that PNP–sirolimus has prolonged circulation in the blood. In addition, PNP–sirolimus preserved the in vitro killing effect of free sirolimus against cancer cells, and intravenous administration displayed its potent in vivo anticancer efficacy in xenograft tumor mice. In addition, PNP–sirolimus enhanced the radiotherapeutic efficacy of sirolimus both in vitro and in vivo. Clinical application of PNP–sirolimus is a promising strategy for human cancer treatment

The Relationship of Anatomic Variation of Pancreatic Ductal System and Pancreaticobiliary Diseases

The aims of this study were to identify the morphological diversities and anatomical variations of pancreatic ductal system and to define the relationships between pancreatic ductal systems, pancreaticobiliary diseases, and procedure-related complications, including post-ERCP pancreatitis. This study included 582 patients in whom both pancreatic duct (PD) and common bile duct were clearly visible by ERCP. PD systems were categorized into four types according to the relationship between common bile duct and PD. In types A and B, Wirsung duct formed the main PD. In type C, Wirsung duct did not form the main PD. If PD system did not fall into any of these three types, it was categorized as type D. The distribution of types among pancreatic ducts examined was as follows: type A: 491 cases (84.4%), type B: 56 cases (9.6%), type C: 20 cases (3.4%), and type D: 15 cases (2.6%). The anomalous anatomic variations of PD systems were divided into migration, fusion, and duplication anomalies. PD anomalies were noted in 51 patients, of which 19 (3.3%) were fusion anomalies (12 complete pancreas divisum, 7 incomplete pancreas divisum), and 32 (5.5%) were duplication anomalies (5 number variations, 27 form variations). No significant relationships between various PD morphologies and pancreaticobiliary diseases were found. However, post-ERCP hyperamylasemia was more frequently found in types C (41.7%), D (50%) and A (19.8%) than in type B (9.4%). In summary, whether Wirsung duct forms the main PD and the presence or absence of the opening of the Santorini duct are both important factors in determining the development of pancreatitis and hyperamylasemia after ERCP

Acetylation of Histone H3K27 Signals the Transcriptional Elongation for Estrogen Receptor Alpha

As approximately 70% of human breast tumors are estrogen receptor α (ERα)-positive, estrogen and ERα play essential roles in breast cancer development. By interrupting the ERα signaling pathway, endocrine therapy has been proven to be an effective therapeutic strategy. In this study, we identified a mechanism by which Transcription Start Site (TSS)-associated histone H3K27 acetylation signals the Super Elongation Complex (SEC) to regulate transcriptional elongation of the ESR1 (ERα) gene. SEC interacts with H3K27ac on ESR1 TSS through its scaffold protein AFF4. Depletion of AFF4 by siRNA or CRISPR/Cas9 dramatically reduces expression of ESR1 and its target genes, consequently inhibiting breast cancer cell growth. More importantly, a AFF4 mutant which lacks H3K27ac interaction failed to rescue ESR1 gene expression, suggesting H3K27 acetylation at TSS region is a key mark bridging the transition from transcriptional initiation to elongation, and perturbing SEC function can be an alternative strategy for targeting ERα signaling pathway at chromatin level