|
1
|
de Jong DM, Roosterman D, Bruno MJ, van Driel LM, Lammers WJ. Interobserver variability in lymph node evaluation with endoscopic ultrasonography in cholangiocarcinoma. Endosc Int Open 2025; 13:a25775449. [PMID: 40376023 PMCID: PMC12080517 DOI: 10.1055/a-2577-5449] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2024] [Accepted: 04/07/2025] [Indexed: 05/18/2025] Open
Abstract
Background and study aims Accurate preoperative lymph node (LN) assessment is crucial for patients with intrahepatic cholangiocarcinoma (iCCA) and perihilar cholangiocarcinoma (pCCA) because presence of LN metastases significantly reduces survival rates and can contraindicate surgical resection. Endoscopic ultrasound (EUS) provides a reliable method for LN assessment with the advantage of enabling tissue acquisition for pathological confirmation. This study aimed to assess interobserver agreement among endosonographers in evaluating LN characteristics in patients with iCCA and pCCA. Methods A cross-sectional survey study was conducted among 24 endosonographers. Participants reviewed 42 EUS images from iCCA and pCCA patients, classifying LNs based on six characteristics (demarcation, shape, echogenicity, homogeneity, suspiciousness, and need to retrieve tissue). Interobserver agreement was determined using Light's kappa statistics. Accuracy, sensitivity, and specificity in identifying malignant LNs were calculated. Results Overall kappa values indicated moderate to fair agreement on LN characteristics, with Kappa values of 0.24 for demarcation, 0.45 for shape, 0.38 for echogenicity, 0.52 for homogeneity, and 0.36 for suspiciousness. Overall accuracy of endosonographers in correctly identifying malignant LNs was 62%, with individual accuracy ranging from 44 to 75%. Sensitivity was 60% (range: 29%-90%) and specificity was 64% (range: 28%-89%). Conclusions Endosonographic assessment of LN morphology and characterization demonstrates considerable variability among endosonographers. Thus, there is a clear need for standardization in preoperative LN evaluation, including establishing consensus about when to perform tissue acquisition, based on objective criteria such as short-axis diameter. Further research is required to refine and optimize these guidelines.
Collapse
Affiliation(s)
- David Michaël de Jong
- Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, Rotterdam, Netherlands
| | - Daniëlle Roosterman
- Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, Rotterdam, Netherlands
| | - Marco J. Bruno
- Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, Rotterdam, Netherlands
| | - Lydi M.J.W. van Driel
- Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, Rotterdam, Netherlands
| | - Wim J. Lammers
- Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, Rotterdam, Netherlands
| |
Collapse
|
|
2
|
de Jong DM, Chehin K, Meijering TL, Segbers M, van Driel LM, Bruno MJ, Groot Koerkamp B, IJzermans JN, Verburg FA, de Lussanet de la Sabloniere QG, Dwarkasing RS. Hybrid FDG-PET/MRI for Diagnosis and Clinical Management of Patients with Suspected Perihilar Cholangiocarcinoma: A Feasibility Pilot Study. Nucl Med Mol Imaging 2024; 58:364-376. [PMID: 39308493 PMCID: PMC11415321 DOI: 10.1007/s13139-024-00873-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2024] [Revised: 06/14/2024] [Accepted: 07/08/2024] [Indexed: 09/25/2024] Open
Abstract
Purpose Recently introduced hybrid 2-[18 F]-fluoro-2-deoxy-D-glucose (18 F-FDG) Positron Emission Tomography (PET) combined with Magnetic Resonance Imaging (MRI) may aid in proper diagnosis and staging of perihilar cholangiocarcinoma (pCCA). The aim of this study is to assess the effect of 18 F-FDG PET/MRI on diagnosis and clinical decision making in the pre-operative work up of pCCA. Methods In this single-centre pilot study patients with presumed resectable pCCA underwent state-of-the-art 18 F-FDG hybrid PET/MRI using digital silicone photomultiplier detectors integrated within a 3-Tesla bore. Data were collected on several baseline and imaging characteristics. The primary outcome measure was the added diagnostic information and the effect on clinical decision making. Secondary aim was to correlate quantitative PET signal intensity to patient- and tumour characteristics. High and low SUVmax subgroups related to the mean value were made. Significance of lesion- and patient characteristics with the high and low SUVmax subgroups, as well as TLR and TBR, was evaluated with Fisher's exact test or Mann-Whitney-U test. Results In total 14 patients were included (mean age 62.4 years, 64% male). Final diagnosis was pCCA in 10 patients (71.4%), follicular lymphoma in one patient (7.1%) and benign disease in the remaining three patients. FDG-PET/MRI added valuable diagnostic information in six (43%) patients and affected clinical decision making in two of these patients (14%) by increasing confidence for malignancy which lead to the decision for surgery on short term. High SUVmax values were seen in half of cases with pCCA and half of cases with non-cancerous lesions. In addition, high SUVmax values were directly associated with primary sclerosing cholangitis when present (p = 0.03). Conclusion Simultaneous 18 F-FDG-PET/MRI added diagnostic information in six of fourteen patients and influenced clinical decision making in two patients (14%) with presumed resectable pCCA.
Collapse
Affiliation(s)
- D. M. de Jong
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, the Netherlands
| | - K. Chehin
- Department of Radiology and Nuclear Medicine, Erasmus MC University Medical Center, Rotterdam, the Netherlands
| | - T. L.N. Meijering
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, the Netherlands
| | - M. Segbers
- Department of Radiology and Nuclear Medicine, Erasmus MC University Medical Center, Rotterdam, the Netherlands
| | - L. M.J.W. van Driel
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, the Netherlands
| | - M. J. Bruno
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, the Netherlands
| | - B. Groot Koerkamp
- Department of Surgery, Erasmus MC University Medical Center, Rotterdam, the Netherlands
| | - J. N.M. IJzermans
- Department of Surgery, Erasmus MC University Medical Center, Rotterdam, the Netherlands
| | - F. A. Verburg
- Department of Radiology and Nuclear Medicine, Erasmus MC University Medical Center, Rotterdam, the Netherlands
| | | | - R. S. Dwarkasing
- Department of Radiology and Nuclear Medicine, Erasmus MC University Medical Center, Rotterdam, the Netherlands
| |
Collapse
|
|
3
|
Chen J, Wang D, Wu G, Xiong F, Liu W, Wang Q, Kuai Y, Huang W, Qi Y, Wang B, Chen Y. STUB1-mediated K63-linked ubiquitination of UHRF1 promotes the progression of cholangiocarcinoma by maintaining DNA hypermethylation of PLA2G2A. J Exp Clin Cancer Res 2024; 43:260. [PMID: 39267107 PMCID: PMC11395162 DOI: 10.1186/s13046-024-03186-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2024] [Accepted: 09/07/2024] [Indexed: 09/14/2024] Open
Abstract
BACKGROUND Cholangiocarcinoma (CCA) is a highly malignant tumor characterized by a lack of effective targeted therapeutic strategies. The protein UHRF1 plays a pivotal role in the preservation of DNA methylation and works synergistically with DNMT1. Posttranscriptional modifications (PTMs), such as ubiquitination, play indispensable roles in facilitating this process. Nevertheless, the specific PTMs that regulate UHRF1 in CCA remain unidentified. METHODS We confirmed the interaction between STUB1 and UHRF1 through mass spectrometry analysis. Furthermore, we investigated the underlying mechanisms of the STUB1-UHRF1/DNMT1 axis via co-IP experiments, denaturing IP ubiquitination experiments, nuclear‒cytoplasmic separation and immunofluorescence experiments. The downstream PLA2G2A gene, regulated by the STUB1-UHRF1/DNMT1 axis, was identified via RNA-seq. The negative regulatory mechanism of PLA2G2A was explored via bisulfite sequencing PCR (BSP) experiments to assess changes in promoter methylation. The roles of PLA2G2A and STUB1 in the proliferation, invasion, and migration of CCA cells were assessed using the CCK-8 assay, colony formation assay, Transwell assay, wound healing assay and xenograft mouse model. We evaluated the effects of STUB1/UHRF1 on cholangiocarcinoma by utilizing a primary CCA mouse model. RESULTS This study revealed that STUB1 interacts with UHRF1, resulting in an increase in the K63-linked ubiquitination of UHRF1. Consequently, this facilitates the nuclear translocation of UHRF1 and enhances its binding affinity with DNMT1. The STUB1-UHRF1/DNMT1 axis led to increased DNA methylation of the PLA2G2A promoter, subsequently repressing its expression. Increased STUB1 expression in CCA was inversely correlated with tumor progression and overall survival. Conversely, PLA2G2A functions as a tumor suppressor in CCA by inhibiting cell proliferation, invasion and migration. CONCLUSIONS These findings suggest that the STUB1-mediated ubiquitination of UHRF1 plays a pivotal role in tumor progression by epigenetically silencing PLA2G2A, underscoring the potential of STUB1 as both a prognostic biomarker and therapeutic target for CCA.
Collapse
Affiliation(s)
- Junsheng Chen
- Department of Biliary-Pancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, Hubei, 430074, China
| | - Da Wang
- Department of Biliary-Pancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, Hubei, 430074, China
| | - Guanhua Wu
- Department of Biliary-Pancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, Hubei, 430074, China
| | - Fei Xiong
- Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China
| | - Wenzheng Liu
- Department of Biliary-Pancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, Hubei, 430074, China
| | - Qi Wang
- Department of Biliary-Pancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, Hubei, 430074, China
| | - Yiyang Kuai
- Department of Biliary-Pancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, Hubei, 430074, China
| | - Wenhua Huang
- Department of Emergency, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, Hubei, 430074, China
| | - Yongqiang Qi
- Key Laboratory of Laparoscopic Technology of Zhejiang Province, Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, China
| | - Bing Wang
- Department of Biliary-Pancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, Hubei, 430074, China.
| | - Yongjun Chen
- Department of Biliary-Pancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, Hubei, 430074, China.
| |
Collapse
|
|
4
|
Yu M, Lu L, Wu R. Perihilar cholangiocarcinoma resection: Is it beneficial for survival in elderly patients? GASTROENTEROLOGIA Y HEPATOLOGIA 2024; 47:691-701. [PMID: 37806347 DOI: 10.1016/j.gastrohep.2023.10.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Revised: 09/25/2023] [Accepted: 10/03/2023] [Indexed: 10/10/2023]
Abstract
INTRODUCTION As the population ages, surgeons are growing frequently faced with hard choices among a vast array of treatment options for the elderly. This study was to investigate safety and efficacy of resection in elderly patients with perihilar cholangiocarcinoma (PHCC). PATIENTS AND METHODS Literature reading and meta-analysis unveiled that elderly PHCC patients held a higher risk of death within 90 days after hepatectomy relative to younger patients, but their 5-year overall survival and disease-free survival were comparable. Among PHCC patients who underwent hepatectomy, the proportion of elderly patients with tumor classification Bismuth I-II and tumor stage pStage 1-3 was significantly higher than that of younger patients. RESULTS Curative resection R0 was more common in elderly patients than younger patients, but the difference was not statistically significant. Because of more comorbidities and less physiological reserve of elderly patients, they seemed to suffer more postoperative complications. CONCLUSION Considering improved life expectancy, it is crucial to treat elderly PHCC patients appropriately and attempts should be made to radical surgery based on comorbidities and functional status.
Collapse
Affiliation(s)
- Min Yu
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China.
| | - Lina Lu
- Digestive Department, Jinhua Wenrong Hospital, Jinhua, China
| | - Rongjin Wu
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China
| |
Collapse
|
|
5
|
Wheless M, Agarwal R, Goff L, Lockney N, Padmanabhan C, Heumann T. Current Standards, Multidisciplinary Approaches, and Future Directions in the Management of Extrahepatic Cholangiocarcinoma. Curr Treat Options Oncol 2024; 25:127-160. [PMID: 38177560 PMCID: PMC10824875 DOI: 10.1007/s11864-023-01153-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/19/2023] [Indexed: 01/06/2024]
Abstract
OPINION STATEMENT Biliary tract cancers are molecularly and anatomically diverse cancers which include intrahepatic cholangiocarcinoma, extrahepatic (perihilar and distal) cholangiocarcinoma, and gallbladder cancer. While recognized as distinct entities, the rarer incidence of these cancers combined with diagnostic challenges in classifying anatomic origin has resulted in clinical trials and guideline recommended strategies being generalized patients with all types of biliary tract cancer. In this review, we delve into the unique aspects, subtype-specific clinical trial outcomes, and multidisciplinary management of patients with extrahepatic cholangiocarcinoma. When resectable, definitive surgery followed by adjuvant chemotherapy (sometimes with selective radiation/chemoradiation) is current standard of care. Due to high recurrence rates, there is growing interest in the use of upfront/neoadjuvant therapy to improve surgical outcomes and to downstage patients who may not initially be resectable. Select patients with perihilar cholangiocarcinoma are being successfully treated with novel approaches such as liver transplant. In the advanced disease setting, combination gemcitabine and cisplatin remains the standard base for systemic therapy and was recently improved upon with the addition of immune checkpoint blockade to the chemotherapy doublet in the recently reported TOPAZ-1 and KEYNOTE-966 trials. Second-line all-comer treatments for these patients remain limited in both options and efficacy, so clinical trial participation should be strongly considered. With increased use of molecular testing, detection of actionable mutations and opportunities to receive indicated targeted therapies are on the rise and are the most significant driver of improved survival for patients with advanced stage disease. Though these targeted therapies are currently reserved for the second or later line, future trials are looking at moving these to earlier treatment settings and use in combination with chemotherapy and immunotherapy. In addition to cross-disciplinary management with surgical, medical, and radiation oncology, patient-centered care should also include collaboration with advanced endoscopists, palliative care specialists, and nutritionists to improve global patient outcomes.
Collapse
Affiliation(s)
- Margaret Wheless
- Department of Medicine, Division of Hematology Oncology, Vanderbilt University Medical Center, 2220 Pierce Avenue, Preston Research Building Suite 798, Nashville, TN, 37232, USA
| | - Rajiv Agarwal
- Department of Medicine, Division of Hematology Oncology, Vanderbilt University Medical Center, 2220 Pierce Avenue, Preston Research Building Suite 798, Nashville, TN, 37232, USA
- Vanderbilt-Ingram Cancer Center, Nashville, TN, USA
| | - Laura Goff
- Department of Medicine, Division of Hematology Oncology, Vanderbilt University Medical Center, 2220 Pierce Avenue, Preston Research Building Suite 798, Nashville, TN, 37232, USA
- Vanderbilt-Ingram Cancer Center, Nashville, TN, USA
| | - Natalie Lockney
- Vanderbilt-Ingram Cancer Center, Nashville, TN, USA
- Department of Radiation Oncology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Chandrasekhar Padmanabhan
- Vanderbilt-Ingram Cancer Center, Nashville, TN, USA
- Department of Surgery, Division of Surgical Oncology & Endocrine Surgery, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Thatcher Heumann
- Department of Medicine, Division of Hematology Oncology, Vanderbilt University Medical Center, 2220 Pierce Avenue, Preston Research Building Suite 798, Nashville, TN, 37232, USA.
- Vanderbilt-Ingram Cancer Center, Nashville, TN, USA.
| |
Collapse
|
|
6
|
Mehrabi A, Golriz M, Ramouz A, Khajeh E, Hammad A, Hackert T, Müller-Stich B, Strobel O, Ali-Hasan-Al-Saegh S, Ghamarnejad O, Al-Saeedi M, Springfeld C, Rupp C, Mayer P, Mieth M, Goeppert B, Hoffmann K, Büchler MW. Promising Outcomes of Modified ALPPS for Staged Hepatectomy in Cholangiocarcinoma. Cancers (Basel) 2023; 15:5613. [PMID: 38067316 PMCID: PMC10705795 DOI: 10.3390/cancers15235613] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2023] [Revised: 11/13/2023] [Accepted: 11/22/2023] [Indexed: 09/14/2024] Open
Abstract
Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) is a two-stage procedure that can potentially cure patients with large cholangiocarcinoma. The current study evaluates the impact of modifications on the outcomes of ALPPS in patients with cholangiocarcinoma. In this single-center study, a series of 30 consecutive patients with cholangiocarcinoma (22 extrahepatic and 8 intrahepatic) who underwent ALPPS between 2011 and 2021 was evaluated. The ALPPS procedure in our center was modified in 2016 by minimizing the first stage of the surgical procedure through biliary externalization after the first stage, antibiotic administration during the interstage phase, and performing biliary reconstructions during the second stage. The rate of postoperative major morbidity and 90-day mortality, as well as the one- and three-year disease-free and overall survival rates were calculated and compared between patients operated before and after 2016. The ALPPS risk score before the second stage of the procedure was lower in patients who were operated on after 2016 (before 2016: median 6.4; after 2016: median 4.4; p = 0.010). Major morbidity decreased from 42.9% before 2016 to 31.3% after 2016, and the 90-day mortality rate decreased from 35.7% before 2016 to 12.5% after 2016. The three-year survival rate increased from 40.8% before 2016 to 73.4% after 2016. Our modified ALPPS procedure improved perioperative and postoperative outcomes in patients with extrahepatic and intrahepatic cholangiocarcinoma. Minimizing the first step of the ALPPS procedure was key to these improvements.
Collapse
Affiliation(s)
- Arianeb Mehrabi
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, 69120 Heidelberg, Germany
- Liver Cancer Center Heidelberg (LCCH), Heidelberg University Hospital, 69120 Heidelberg, Germany
| | - Mohammad Golriz
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, 69120 Heidelberg, Germany
- Liver Cancer Center Heidelberg (LCCH), Heidelberg University Hospital, 69120 Heidelberg, Germany
| | - Ali Ramouz
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, 69120 Heidelberg, Germany
| | - Elias Khajeh
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, 69120 Heidelberg, Germany
| | - Ahmed Hammad
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, 69120 Heidelberg, Germany
| | - Thilo Hackert
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, 69120 Heidelberg, Germany
- Liver Cancer Center Heidelberg (LCCH), Heidelberg University Hospital, 69120 Heidelberg, Germany
| | - Beat Müller-Stich
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, 69120 Heidelberg, Germany
- Liver Cancer Center Heidelberg (LCCH), Heidelberg University Hospital, 69120 Heidelberg, Germany
| | - Oliver Strobel
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, 69120 Heidelberg, Germany
- Liver Cancer Center Heidelberg (LCCH), Heidelberg University Hospital, 69120 Heidelberg, Germany
| | - Sadeq Ali-Hasan-Al-Saegh
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, 69120 Heidelberg, Germany
| | - Omid Ghamarnejad
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, 69120 Heidelberg, Germany
| | - Mohammed Al-Saeedi
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, 69120 Heidelberg, Germany
| | - Christoph Springfeld
- Liver Cancer Center Heidelberg (LCCH), Heidelberg University Hospital, 69120 Heidelberg, Germany
- Department of Medical Oncology, National Center for Tumor Diseases, Heidelberg University Hospital, 69120 Heidelberg, Germany
| | - Christian Rupp
- Department of Internal Medicine, Heidelberg University Hospital, 69120 Heidelberg, Germany
| | - Philipp Mayer
- Department of Interventional Radiology, Heidelberg University Hospital, 69120 Heidelberg, Germany
| | - Markus Mieth
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, 69120 Heidelberg, Germany
| | - Benjamin Goeppert
- Liver Cancer Center Heidelberg (LCCH), Heidelberg University Hospital, 69120 Heidelberg, Germany
- Institute of Pathology, Heidelberg University Hospital, 69120 Heidelberg, Germany
| | - Katrin Hoffmann
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, 69120 Heidelberg, Germany
- Liver Cancer Center Heidelberg (LCCH), Heidelberg University Hospital, 69120 Heidelberg, Germany
| | - Markus W. Büchler
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, 69120 Heidelberg, Germany
| |
Collapse
|
|
7
|
Wu G, Wang D, Xiong F, Liu W, Wang Q, Chen J, Wang B, Chen Y. Upregulation of RSPO3 via targeted promoter DNA demethylation inhibits the progression of cholangiocarcinoma. Clin Epigenetics 2023; 15:177. [PMID: 37932819 PMCID: PMC10629118 DOI: 10.1186/s13148-023-01592-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2023] [Accepted: 10/25/2023] [Indexed: 11/08/2023] Open
Abstract
BACKGROUND Cholangiocarcinoma (CCA) refers to a collection of malignant tumors that develop from the biliary epithelium. Extensive clinical evidence and epidemiological observations indicate a concerning increase in both the incidence and mortality rates of CCA. Surgical resection is currently the sole available cure for CCA. However, it is unfortunate that only a fraction of patients has access to surgery at the time of diagnosis. Moreover, there is a high incidence of cancer recurrence after resection, and systemic treatments have limited efficacy. Therefore, the identification of novel biomarkers for CCA-targeted molecular therapy remains a crucial task in oncology research. RESULTS Our study demonstrated that low expression of RSPO3 was associated with poorer survival rates in patients with CCA. We found that the RSPO3 promoter DNA was hypermethylated in CCA, which was correlated with the low expression of RSPO3. The expression of RSPO3 was influenced by the balance between the DNA methyltransferase DNMT3a and the DNA demethylase TET1 in CCA. In vitro and in vivo experiments showed that targeting RSPO3 promoter DNA methylation using dCas9DNMT3a promoted tumorigenicity of CCA, while targeted RSPO3 promoter DNA demethylation using dCas9TET1CD inhibited CCA tumorigenicity. Additionally, in our primary CCA model, knockdown of Rspo3 promoted CCA progression, whereas overexpression of Rspo3 inhibited CCA progression. CONCLUSIONS Our findings suggest that increased methylation and decreased expression of RSPO3 may indicate a poor prognosis in CCA. Restoring RSPO3 expression by targeting promoter DNA demethylation could offer insights for precise treatment of CCA.
Collapse
Affiliation(s)
- Guanhua Wu
- Department of Biliary-Pancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Road, Wuhan, 430074, Hubei, China
| | - Da Wang
- Department of Biliary-Pancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Road, Wuhan, 430074, Hubei, China
| | - Fei Xiong
- Department of Biliary-Pancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Road, Wuhan, 430074, Hubei, China
| | - Wenzheng Liu
- Department of Biliary-Pancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Road, Wuhan, 430074, Hubei, China
| | - Qi Wang
- Department of Biliary-Pancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Road, Wuhan, 430074, Hubei, China
| | - Junsheng Chen
- Department of Biliary-Pancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Road, Wuhan, 430074, Hubei, China
| | - Bing Wang
- Department of Biliary-Pancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Road, Wuhan, 430074, Hubei, China.
| | - Yongjun Chen
- Department of Biliary-Pancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Road, Wuhan, 430074, Hubei, China.
| |
Collapse
|
|
8
|
Vita F, Olaizola I, Amato F, Rae C, Marco S, Banales JM, Braconi C. Heterogeneity of Cholangiocarcinoma Immune Biology. Cells 2023; 12:cells12060846. [PMID: 36980187 PMCID: PMC10047186 DOI: 10.3390/cells12060846] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2023] [Revised: 03/04/2023] [Accepted: 03/06/2023] [Indexed: 03/11/2023] Open
Abstract
Cholangiocarcinomas (CCAs) are aggressive tumors arising along the biliary tract epithelium, whose incidence and mortality are increasing. CCAs are highly desmoplastic cancers characterized by a dense tumor microenvironment (TME), in which each single component plays a fundamental role in shaping CCA initiation, progression and resistance to therapies. The crosstalk between cancer cells and TME can affect the recruitment, infiltration and differentiation of immune cells. According to the stage of the disease and to intra- and inter-patient heterogeneity, TME may contribute to either protumoral or antitumoral activities. Therefore, a better understanding of the effect of each immune cell subtype may open the path to new personalized immune therapeutic strategies for the management of CCA. In this review, we describe the role of immune cells in CCA initiation and progression, and their crosstalk with both cancer-associated fibroblasts (CAFs) and the cancer-stem-cell-like (CSC) niche.
Collapse
Affiliation(s)
- Francesca Vita
- School of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, UK; (F.V.); (F.A.); (C.R.); (S.M.)
- Department of Oncology, University of Turin, 10043 Turin, Italy
| | - Irene Olaizola
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute–Donostia University Hospital, University of the Basque Country (UPV/EHU), 20014 San Sebastian, Spain; (I.O.); (J.M.B.)
| | - Francesco Amato
- School of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, UK; (F.V.); (F.A.); (C.R.); (S.M.)
| | - Colin Rae
- School of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, UK; (F.V.); (F.A.); (C.R.); (S.M.)
| | - Sergi Marco
- School of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, UK; (F.V.); (F.A.); (C.R.); (S.M.)
| | - Jesus M. Banales
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute–Donostia University Hospital, University of the Basque Country (UPV/EHU), 20014 San Sebastian, Spain; (I.O.); (J.M.B.)
- IKERBASQUE, Basque Foundation for Science, 48009 Bilbao, Spain
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, “Instituto de Salud Carlos III”), 28029 Madrid, Spain
- Department of Biochemistry and Genetics, School of Sciences, University of Navarra, 31008 Pamplona, Spain
| | - Chiara Braconi
- School of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, UK; (F.V.); (F.A.); (C.R.); (S.M.)
- Beatson West of Scotland Cancer Centre, Glasgow G12 0YN, UK
- Correspondence:
| |
Collapse
|
|
9
|
de Jong DM, van de Vondervoort S, Dwarkasing RS, Doukas M, Voermans RP, Verdonk RC, Polak WG, de Jonge J, Koerkamp BG, Bruno MJ, van Driel LM. Endoscopic ultrasound in patients with resectable perihilar cholangiocarcinoma: impact on clinical decision-making. Endosc Int Open 2023; 11:E162-E168. [PMID: 36741342 PMCID: PMC9894690 DOI: 10.1055/a-2005-3679] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Accepted: 11/03/2022] [Indexed: 01/01/2023] Open
Abstract
Background and study aims Accurate assessment of the lymph node (LN) status is crucial in resectable perihilar cholangiocarcinoma (pCCA) to prevent major surgery in patients with extraregional metastatic LNs (MLNs). This study investigates the added value of preoperative endoscopic ultrasound (EUS) with or without tissue acquisition (TA) for the detection of MLNs in patients with resectable pCCA. Patients and methods In this retrospective, multicenter cohort study, patients with potentially resectable pCCA who underwent EUS preoperatively between 2010-2020, were included. The clinical impact of EUS-TA was defined as the percentage of patients who did not undergo surgical resection due to MLNs found with EUS-TA. Findings of cross-sectional imaging were compared with EUS-TA findings and surgery. Results EUS was performed on 141 patients, of whom 107 (76 %) had suspicious LNs on cross-sectional imaging. Surgical exploration was prevented in 20 patients (14 %) because EUS-TA detected MLNs, of which 17 (85 %) were extraregional. Finally, 74 patients (52 %) underwent surgical exploration followed by complete resection in 40 (28 %). MLNs were identified at definitive pathology in 24 (33 %) patients, of which 9 (38 %) were extraregional and 15 (63 %) regional. Conclusions EUS-TA may be of value in patients with potentially resectable pCCA based on preoperative cross-sectional imaging, regardless of lymphadenopathy at cross-sectional imaging. A prospective study in which a comprehensive EUS investigation with LN assessment and EUS-TA of LNs is performed routinely should confirm this promise.
Collapse
Affiliation(s)
- David M. de Jong
- Erasmus MC Cancer Institute University Medical Center Rotterdam, Department of Gastroenterology and Hepatology, Rotterdam, Netherlands
| | - Sanne van de Vondervoort
- Erasmus MC Cancer Institute University Medical Center Rotterdam, Department of Gastroenterology and Hepatology, Rotterdam, Netherlands
| | - Roy S. Dwarkasing
- Erasmus MC Cancer Institute University Medical Center Rotterdam, Department of Radiology and Nuclear Medicine, Rotterdam, Netherlands
| | - Michael Doukas
- Erasmus MC Cancer Institute University Medical Center Rotterdam, Department of Pathology, Rotterdam, Netherlands
| | - Rogier P. Voermans
- Amsterdam University Medical Center, Department of Gastroenterology and Hepatology, Amsterdam, Netherlands ,Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, Netherlands ,Cancer Center Amsterdam, Cancer Treatment and Quality of Life, Amsterdam, Netherlands
| | - Robert C. Verdonk
- St. Antonius Hospital, Department of Gastroenterology and Hepatology, Nieuwegein, Netherlands
| | - Wojciech G. Polak
- Erasmus MC Cancer Institute University Medical Center Rotterdam, Department of Surgery, Rotterdam, Netherlands
| | - Jeroen de Jonge
- Erasmus MC Cancer Institute University Medical Center Rotterdam, Department of Surgery, Rotterdam, Netherlands
| | - Bas Groot Koerkamp
- Erasmus MC Cancer Institute University Medical Center Rotterdam, Department of Surgery, Rotterdam, Netherlands
| | - Marco J. Bruno
- Erasmus MC Cancer Institute University Medical Center Rotterdam, Department of Gastroenterology and Hepatology, Rotterdam, Netherlands
| | - Lydi M.J.W. van Driel
- Erasmus MC Cancer Institute University Medical Center Rotterdam, Department of Gastroenterology and Hepatology, Rotterdam, Netherlands
| |
Collapse
|
|
10
|
Vatankhah F, Salimi N, Khalaji A, Baradaran B. Immune checkpoints and their promising prospect in cholangiocarcinoma treatment in combination with other therapeutic approaches. Int Immunopharmacol 2023; 114:109526. [PMID: 36481527 DOI: 10.1016/j.intimp.2022.109526] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Revised: 11/21/2022] [Accepted: 11/27/2022] [Indexed: 12/12/2022]
Abstract
Cholangiocarcinoma (CCA) is one of the malignant tumors that has shown rapid development in incidence and mortality in recent years. Like other types of cancer, patients with CCA experience alterations in the expression of immune checkpoints, indicating the importance of immune checkpoint inhibitors in treating CCA. The results of TCGA analysis in this study revealed a marginal difference in the expression of important immune checkpoints, Programmed cell death 1 (PD-1) and Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and their ligands in CCA samples compared to normal ones. This issue showed the importance of combination therapy in this cancer. This review considers CCA treatment and covers several therapeutic modalities or combined treatment strategies. We also cover the most recent developments in the field and outline the important areas of immune checkpoint molecules as prognostic variables and therapeutic targets in CCA.
Collapse
Affiliation(s)
- Fatemeh Vatankhah
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Neda Salimi
- School of Pharmacy, Guilan University of Medical Sciences, Rasht, Iran
| | - Amirreza Khalaji
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
| |
Collapse
|
|
11
|
Aphivatanasiri C, Sa-Ngiamwibool P, Sangkhamanon S, Intarawichian P, Kunprom W, Thanee M, Prajumwongs P, Khuntikeo N, Titapun A, Jareanrat A, Thanasukarn V, Srisuk T, Luvira V, Eurboonyanun K, Promsorn J, Loilome W, Wee A, Koonmee S. Modification of the eighth AJCC/UICC staging system for perihilar cholangiocarcinoma: An alternative pathological staging system from cholangiocarcinoma-prevalent Northeast Thailand. Front Med (Lausanne) 2022; 9:893252. [PMID: 36250068 PMCID: PMC9561347 DOI: 10.3389/fmed.2022.893252] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2022] [Accepted: 07/25/2022] [Indexed: 11/13/2022] Open
Abstract
AimThis 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.MethodFour 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.ResultsMultivariate 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.).ConclusionThe 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.
Collapse
Affiliation(s)
- Chaiwat Aphivatanasiri
- Cholangiocarcinoma Screening and Care Program (CASCAP), Khon Kaen University, Khon Kaen, Thailand
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand
- Department of Pathology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Prakasit Sa-Ngiamwibool
- Cholangiocarcinoma Screening and Care Program (CASCAP), Khon Kaen University, Khon Kaen, Thailand
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand
- Department of Pathology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Sakkarn Sangkhamanon
- Cholangiocarcinoma Screening and Care Program (CASCAP), Khon Kaen University, Khon Kaen, Thailand
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand
- Department of Pathology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Piyapharom Intarawichian
- Cholangiocarcinoma Screening and Care Program (CASCAP), Khon Kaen University, Khon Kaen, Thailand
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand
- Department of Pathology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Waritta Kunprom
- Cholangiocarcinoma Screening and Care Program (CASCAP), Khon Kaen University, Khon Kaen, Thailand
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand
- Department of Pathology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Malinee Thanee
- Cholangiocarcinoma Screening and Care Program (CASCAP), Khon Kaen University, Khon Kaen, Thailand
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand
- Department of Pathology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Piya Prajumwongs
- Cholangiocarcinoma Screening and Care Program (CASCAP), Khon Kaen University, Khon Kaen, Thailand
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand
- Department of Pathology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Narong Khuntikeo
- Cholangiocarcinoma Screening and Care Program (CASCAP), Khon Kaen University, Khon Kaen, Thailand
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand
- Department of Surgery, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Attapol Titapun
- Cholangiocarcinoma Screening and Care Program (CASCAP), Khon Kaen University, Khon Kaen, Thailand
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand
- Department of Surgery, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Apiwat Jareanrat
- Cholangiocarcinoma Screening and Care Program (CASCAP), Khon Kaen University, Khon Kaen, Thailand
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand
- Department of Surgery, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Vasin Thanasukarn
- Cholangiocarcinoma Screening and Care Program (CASCAP), Khon Kaen University, Khon Kaen, Thailand
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand
- Department of Surgery, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Tharatip Srisuk
- Cholangiocarcinoma Screening and Care Program (CASCAP), Khon Kaen University, Khon Kaen, Thailand
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand
- Department of Surgery, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Vor Luvira
- Cholangiocarcinoma Screening and Care Program (CASCAP), Khon Kaen University, Khon Kaen, Thailand
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand
- Department of Surgery, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Kulyada Eurboonyanun
- Cholangiocarcinoma Screening and Care Program (CASCAP), Khon Kaen University, Khon Kaen, Thailand
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand
- Department of Radiology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Julaluck Promsorn
- Cholangiocarcinoma Screening and Care Program (CASCAP), Khon Kaen University, Khon Kaen, Thailand
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand
- Department of Radiology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Watcharin Loilome
- Cholangiocarcinoma Screening and Care Program (CASCAP), Khon Kaen University, Khon Kaen, Thailand
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Aileen Wee
- Department of Pathology, National University Hospital, Singapore, Singapore
| | - Supinda Koonmee
- Cholangiocarcinoma Screening and Care Program (CASCAP), Khon Kaen University, Khon Kaen, Thailand
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand
- Department of Pathology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
- *Correspondence: Supinda Koonmee
| |
Collapse
|
|
12
|
Sarantis P, Tzanetatou ED, Ioakeimidou E, Vallilas C, Androutsakos T, Damaskos C, Garmpis N, Garmpi A, Papavassiliou AG, Karamouzis MV. Cholangiocarcinoma: the role of genetic and epigenetic factors; current and prospective treatment with checkpoint inhibitors and immunotherapy. Am J Transl Res 2021; 13:13246-13260. [PMID: 35035673 PMCID: PMC8748131] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Accepted: 11/09/2021] [Indexed: 06/14/2023]
Abstract
Cholangiocarcinoma (CCA) represents 3% of all gastrointestinal cancers worldwide and is the second most common primary liver tumor after hepatocellular carcinoma. CCA is an aggressive tumor that involves the intrahepatic, perihilar and distal biliary tree, with a poor prognosis and an increasing incidence worldwide. Various genetic and epigenetic factors have been implicated in CCA development. Gene mutations involving apoptosis control and cell cycle evolution, histone modifications, methylation dysregulation and abnormal expression of non-coding RNA are the most important of these factors. Regarding treatment, surgical resection, cisplatin and gemcitabine have long been the most common treatment options, but 5-year survival (7-20%) is disappointing. For that reason, inhibitors and small molecules related to specific mutations and molecular pathways have been introduced. Among them, immunotherapy seems to be a promising treatment in CCA, with multiple regimens being under clinical trial studies. The combinatorial therapy of traditional CCA treatment with tyrosine kinase inhibitors and/or immunotherapy seem to be the future, depending on the molecular profile of each patient's tumor.
Collapse
Affiliation(s)
- Panagiotis Sarantis
- Molecular Oncology Unit, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens11527 Athens, Greece
| | - Eleftheria Dikoglou Tzanetatou
- Molecular Oncology Unit, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens11527 Athens, Greece
| | - Evangelia Ioakeimidou
- Molecular Oncology Unit, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens11527 Athens, Greece
| | - Christos Vallilas
- Molecular Oncology Unit, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens11527 Athens, Greece
| | - Theodoros Androutsakos
- Pathophysiology Department, Medical School, National and Kapodistrian University of Athens11527 Athens, Greece
| | - Christos Damaskos
- N.S. Christeas Laboratory of Experimental Surgery and Surgical Research, Medical School, National and Kapodistrian University of Athens11527 Athens, Greece
- Renal Transplantation Unit, Laiko General Hospital11527 Athens, Greece
| | - Nikolaos Garmpis
- N.S. Christeas Laboratory of Experimental Surgery and Surgical Research, Medical School, National and Kapodistrian University of Athens11527 Athens, Greece
- Second Department of Propedeutic Surgery, Laiko General Hospital, Medical School, National and Kapodistrian University of Athens11527 Athens, Greece
| | - Anna Garmpi
- First Department of Propedeutic Internal Medicine, Laiko General Hospital, Medical School, National and Kapodistrian University of Athens11527 Athens, Greece
| | - Athanasios G Papavassiliou
- Molecular Oncology Unit, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens11527 Athens, Greece
| | - Michalis V Karamouzis
- Molecular Oncology Unit, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens11527 Athens, Greece
| |
Collapse
|
|
13
|
Wang D, Xiong F, Wu G, Liu W, Wang B, Chen Y. MiR-155-5p suppresses SOX1 to promote proliferation of cholangiocarcinoma via RAF/MEK/ERK pathway. Cancer Cell Int 2021; 21:656. [PMID: 34876142 PMCID: PMC8650398 DOI: 10.1186/s12935-021-02374-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2021] [Accepted: 11/29/2021] [Indexed: 11/21/2022] Open
Abstract
Background Accumulating evidence has demonstrated the close relation of SOX1 with tumorigenesis and tumor progression. Upregulation of SOX1 was recently shown to suppress growth of human cancers. However, the expression and role of SOX1 in cholangiocarcinoma (CCA) is not well characterized. Methods Expression levels of SOX1 in CCA tissues and normal bile duct tissues were examined using public GEO database. Western blot and immunohistochemistry were used to confirm the expression levels. Cell proliferation assay (CCK-8) and colony formation assay were performed to assess proliferation of CCA cells. A mouse model of subcutaneous transplantable tumors was used to evaluated proliferation of CCA in vivo. The putative regulating factor of SOX1 were determined using Targetscan and dual-luciferase reporter assay. Results SOX1 was downregulated in CCA tissues. Overexpression of SOX1 significantly inhibited cell proliferation in vitro and suppressed tumor growth in vivo. miR-155-5p directly targeted the 3′-untranslated region (3′UTR) of SOX1 and inhibited expression of SOX1, resulting in the activation of RAF, MEK and ERK phosphorylation, and thus CCA proliferation. However, restoration of SOX1 expression in miR-155-5p overexpressing cell lines decreased the phosphorylation level of RAF, MEK and ERK, as well as the proliferation of CCA cells. Conclusion MiR-155-5p decreased the expression of SOX1 by binding to its 3′UTR, which activated the RAF/MEK/ERK signaling pathway and promoted CCA progression. Supplementary Information The online version contains supplementary material available at 10.1186/s12935-021-02374-0.
Collapse
Affiliation(s)
- Da Wang
- Department of Biliary-Pancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang avenue 1095, Wuhan, Hubei, China.,Department of General Surgery, The Fifth People's Hospital of Shanghai, Fudan University, Shanghai, China
| | - Fei Xiong
- Department of Biliary-Pancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang avenue 1095, Wuhan, Hubei, China
| | - Guanhua Wu
- Department of Biliary-Pancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang avenue 1095, Wuhan, Hubei, China
| | - Wenzheng Liu
- Department of Biliary-Pancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang avenue 1095, Wuhan, Hubei, China
| | - Bing Wang
- Department of Biliary-Pancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang avenue 1095, Wuhan, Hubei, China.
| | - Yongjun Chen
- Department of Biliary-Pancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang avenue 1095, Wuhan, Hubei, China.
| |
Collapse
|
|
14
|
Rodrigues PM, Olaizola P, Paiva NA, Olaizola I, Agirre-Lizaso A, Landa A, Bujanda L, Perugorria MJ, Banales JM. Pathogenesis of Cholangiocarcinoma. ANNUAL REVIEW OF PATHOLOGY 2021; 16:433-463. [PMID: 33264573 DOI: 10.1146/annurev-pathol-030220-020455] [Citation(s) in RCA: 79] [Impact Index Per Article: 19.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Cholangiocarcinoma (CCA) encompasses a group of malignancies that can arise at any point in the biliary tree. Although considered a rare cancer, the incidence of CCA is increasing globally. The silent and asymptomatic nature of these tumors, particularly in their early stages, in combination with their high aggressiveness, intra- and intertumor heterogeneity, and chemoresistance, significantly compromises the efficacy of current therapeutic options, contributing to a dismal prognosis. During the last few years, increasing efforts have been made to unveil the etiologies and pathogenesis of these tumors and to develop more effective therapies. In this review, we summarize current findings in the field of CCA, mainly focusing on the mechanisms of pathogenesis, cells of origin, genomic and epigenetic abnormalities, molecular alterations, chemoresistance, and therapies.
Collapse
Affiliation(s)
- Pedro M Rodrigues
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), 20014 San Sebastian, Spain; ,
- National Institute for the Study of Liver and Gastrointestinal Diseases, CIBERehd, Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Paula Olaizola
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), 20014 San Sebastian, Spain; ,
| | - Nuno A Paiva
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), 20014 San Sebastian, Spain; ,
| | - Irene Olaizola
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), 20014 San Sebastian, Spain; ,
| | - Alona Agirre-Lizaso
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), 20014 San Sebastian, Spain; ,
| | - Ana Landa
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), 20014 San Sebastian, Spain; ,
| | - Luis Bujanda
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), 20014 San Sebastian, Spain; ,
- National Institute for the Study of Liver and Gastrointestinal Diseases, CIBERehd, Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Maria J Perugorria
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), 20014 San Sebastian, Spain; ,
- National Institute for the Study of Liver and Gastrointestinal Diseases, CIBERehd, Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Jesus M Banales
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), 20014 San Sebastian, Spain; ,
- National Institute for the Study of Liver and Gastrointestinal Diseases, CIBERehd, Instituto de Salud Carlos III, 28029 Madrid, Spain
- Ikerbasque, Basque Foundation for Science, 48013 Bilbao, Spain
| |
Collapse
|
|
15
|
Hue JJ, Sugumar K, Markt SC, Mohamed A, Selfridge JE, Bajor D, Rothermel LD, Hardacre JM, Ammori JB, Winter JM, Ocuin LM. Reassessing the role of surgery in the elderly or chronically sick with proximal extrahepatic cholangiocarcinoma. Surgery 2020; 169:233-239. [PMID: 33087251 DOI: 10.1016/j.surg.2020.09.011] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2020] [Revised: 09/05/2020] [Accepted: 09/10/2020] [Indexed: 12/26/2022]
Abstract
BACKGROUND Most data on postoperative outcomes among patients with proximal extrahepatic cholangiocarcinoma are reported by single institutions. The purpose of this study was to analyze postoperative outcomes stratified by age and comorbidities. METHODS Patients with proximal extrahepatic cholangiocarcinoma who underwent a resection were identified in the National Cancer Database. Pathologic, postoperative, and survival outcomes were compared based on age and Charlson-Deyo comorbidity index. RESULTS Among the 1,579 patients, the average age was 66 years, and 9.4% of patients were older than 80 years. Most patients had a Charlson-Deyo score of 0 (72.4%), with the minority having scores of 1 (20.5%) or ≥2 (7.1%). Patients ≥80 years had a higher 90-day mortality rate compared with patients 65 to 79 and <65 years (21.3% vs 12.0% vs 7.4%, P < .001). Patients with a Charlson-Deyo score ≥2 had longer duration of stay, greater likelihood of requiring an unplanned readmission, and a higher 90-day mortality rate compared with patients with a lower comorbidity index. Median survival of patients <65, 65 to 79, and ≥80 years was 31, 24, and 17 months, respectively. A similar trend was seen with increasing Charlson-Deyo score (0: 27 months, 1: 25 months, ≥2: 20 months). On multivariable analysis, age ≥80 years (hazard ratio = 1.52, P = .01) and Charlson-Deyo score ≥2 (hazard ratio = 1.45, P = .01) were associated with poor survival. CONCLUSION In patients with proximal extrahepatic cholangiocarcinoma, age ≥80 years and greater comorbidity index are associated with increased risk of 90-day mortality and poor overall survival. This suggests that resections in high-risk patient populations should be approached with caution.
Collapse
Affiliation(s)
- Jonathan J Hue
- Department of Surgery, Division of Surgical Oncology, University Hospitals Cleveland Medical Center, OH
| | - Kavin Sugumar
- Department of Surgery, Division of Surgical Oncology, University Hospitals Cleveland Medical Center, OH
| | - Sarah C Markt
- Department of Population and Quantitative Health Sciences, Case Western Reserve University School of Medicine, Cleveland, OH
| | - Amr Mohamed
- Department of Medicine, Division of Hematology/Oncology, University Hospitals Cleveland Medical Center, OH
| | - J Eva Selfridge
- Department of Medicine, Division of Hematology/Oncology, University Hospitals Cleveland Medical Center, OH
| | - David Bajor
- Department of Medicine, Division of Hematology/Oncology, University Hospitals Cleveland Medical Center, OH
| | - Luke D Rothermel
- Department of Surgery, Division of Surgical Oncology, University Hospitals Cleveland Medical Center, OH
| | - Jeffrey M Hardacre
- Department of Surgery, Division of Surgical Oncology, University Hospitals Cleveland Medical Center, OH
| | - John B Ammori
- Department of Surgery, Division of Surgical Oncology, University Hospitals Cleveland Medical Center, OH
| | - Jordan M Winter
- Department of Surgery, Division of Surgical Oncology, University Hospitals Cleveland Medical Center, OH
| | - Lee M Ocuin
- Department of Surgery, Division of Hepatobiliary and Pancreatic Surgery, Atrium Health, Charlotte, NC.
| |
Collapse
|
|
16
|
Impact of Remnant Carcinoma in Situ at the Ductal Stump on Long-Term Outcomes in Patients with Distal Cholangiocarcinoma. World J Surg 2020; 45:291-301. [PMID: 32989580 DOI: 10.1007/s00268-020-05799-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/15/2020] [Indexed: 10/23/2022]
Abstract
BACKGROUND The management of positive ductal margins with carcinoma in situ (R1-CIS) after resection is controversial. The aim of this study was to evaluate the impact of R1-CIS on survival in patients who underwent resection for distal cholangiocarcinoma. METHODS We enrolled 121 consecutive patients with distal cholangiocarcinoma. Poor prognostic factors were investigated by multivariable analysis, and we performed a stratified analysis to evaluate the impact of R1-CIS on survival in patients with or without prognostic factors. RESULTS Multivariable analysis identified node-positive status as the prognostic factor (P = 0.003). Stratified by lymph node status, overall survival (OS) in the R0 group was significantly better than that in the R1-CIS group in node-negative patients (57.1% vs 30.0%; P < 0.050). Although OS was comparable between the two groups in node-positive patients (5-year OS: 22.2% vs 20.0%, respectively; P = not significant). Furthermore, OS in patients in whom R0 was achieved by additional resection was significantly better than that in patients with R1-CIS (5-year OS: 66.7% vs 30.0%, respectively; P < 0.050). CONCLUSIONS Remnant CIS is associated with a poor prognosis in patients with node-negative distal cholangiocarcinoma. Every effort should be made to achieve negative bile duct margins.
Collapse
|
|
17
|
Juratli MA, Hofmann K, Balaban Ü, El Youzouri H, Pession U, Heise M, Mekicar J, Schreckenbach T, Trojan J, Waidmann O, Walter D, Vogl T, Eichler K, Wild P, Schulze F, Brandts C, Bechstein WO, Schnitzbauer AA, Mönch C. [Introduction of an interdisciplinary tumor board leads to improvement of treatment outcome of cholangiocarcinoma (bile duct cancer)]. Chirurg 2020; 91:650-661. [PMID: 31932971 DOI: 10.1007/s00104-019-01100-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
BACKGROUND Cholangiocarcinoma (CCA, bile duct cancer) is a rare malignant disease with a poor prognosis. For several years interdisciplinary tumor boards (TuB) with the participation of experts from various disciplines have been organized to optimize medical treatment for patients suffering from oncological diseases. OBJECTIVE This study addressed the question whether the introduction of TuB leads to a better life expectancy and quality of life for patients with CCA. MATERIAL AND METHODS In this retrospective study 161 patients treated for CCA were investigated. The patient collective was divided in two groups (TuB+ vs. TuB-) and a propensity score matching was carried out. RESULTS The patient group TuB+ included 109 patients (67.7%) and the control group (TuB-) included 52 patients (32.3%). Using propensity score matching 84 patients in the TuB+ and 50 in the TuB group were identified and matched. The survival rates of the matched patients demonstrated an advantage for patients in the TuB+ group (1-year survival rate 61.9%, 5‑year survival rate 23.6%, 10-year survival rate 18.0%) over patients in the TuB-group (1-year survival rate 32.0%, 5‑year survival rate 8.0%, 10-year survival rate 0%) with p < 0.001. The results of the univariate (hazard ratio, HR 0.513, 95% confidence interval, CI 0.350-0.751, p = 0.001) and the multivariate Cox proportional hazard models (HR 0.459, 95% CI 0.303-0.694, p < 0.001) showed a significant benefit in survival for patients in the TuB+ group. CONCLUSION This article shows that the introduction of a TuB meeting can provide a measurable benefit for patients with CCA. Hence it is recommended that all cases of patients with CCA should be discussed in a TuB.
Collapse
Affiliation(s)
- Mazen A Juratli
- Klinik für Allgemein- und Viszeralchirurgie, Universitätsklinikum Frankfurt am Main, Frankfurt am Main, Deutschland
| | - Konstantin Hofmann
- Klinik für Allgemein- und Viszeralchirurgie, Universitätsklinikum Frankfurt am Main, Frankfurt am Main, Deutschland
| | - Ümniye Balaban
- Institut für Biostatistik und mathematische Modellierung, Goethe-Universität Frankfurt am Main, Frankfurt am Main, Deutschland
| | - Hanan El Youzouri
- Klinik für Allgemein- und Viszeralchirurgie, Universitätsklinikum Frankfurt am Main, Frankfurt am Main, Deutschland
| | - Ursula Pession
- Klinik für Allgemein- und Viszeralchirurgie, Universitätsklinikum Frankfurt am Main, Frankfurt am Main, Deutschland
| | - Michael Heise
- Klinik für Allgemein- und Viszeralchirurgie, Universitätsklinikum Frankfurt am Main, Frankfurt am Main, Deutschland
| | - Jernej Mekicar
- Klinik für Allgemein- und Viszeralchirurgie, Universitätsklinikum Frankfurt am Main, Frankfurt am Main, Deutschland
| | - Teresa Schreckenbach
- Klinik für Allgemein- und Viszeralchirurgie, Universitätsklinikum Frankfurt am Main, Frankfurt am Main, Deutschland
| | - Jörg Trojan
- Medizinische Klinik 1: Gastroenterologie und Hepatologie, Pneumologie und Allergologie, Endokrinologie und Diabetologie sowie Ernährungsmedizin, Universitätsklinikum Frankfurt am Main, Frankfurt am Main, Deutschland
| | - Oliver Waidmann
- Medizinische Klinik 1: Gastroenterologie und Hepatologie, Pneumologie und Allergologie, Endokrinologie und Diabetologie sowie Ernährungsmedizin, Universitätsklinikum Frankfurt am Main, Frankfurt am Main, Deutschland
| | - Dirk Walter
- Medizinische Klinik 1: Gastroenterologie und Hepatologie, Pneumologie und Allergologie, Endokrinologie und Diabetologie sowie Ernährungsmedizin, Universitätsklinikum Frankfurt am Main, Frankfurt am Main, Deutschland
| | - Thomas Vogl
- Institut für Diagnostische und Interventionelle Radiologie, Universitätsklinikum Frankfurt am Main, Frankfurt am Main, Deutschland
| | - Katrin Eichler
- Institut für Diagnostische und Interventionelle Radiologie, Universitätsklinikum Frankfurt am Main, Frankfurt am Main, Deutschland
| | - Peter Wild
- Dr. Senckenbergisches Institut für Pathologie, Universitätsklinikum Frankfurt am Main, Frankfurt am Main, Deutschland
| | - Falko Schulze
- Dr. Senckenbergisches Institut für Pathologie, Universitätsklinikum Frankfurt am Main, Frankfurt am Main, Deutschland
| | - Christian Brandts
- Medizinische Klinik II, Hämatologie/Onkologie, Universitätsklinikum Frankfurt, Frankfurt am Main, Deutschland
| | - Wolf O Bechstein
- Klinik für Allgemein- und Viszeralchirurgie, Universitätsklinikum Frankfurt am Main, Frankfurt am Main, Deutschland
| | - Andreas A Schnitzbauer
- Klinik für Allgemein- und Viszeralchirurgie, Universitätsklinikum Frankfurt am Main, Frankfurt am Main, Deutschland
| | - Christian Mönch
- Klinik für Allgemein‑, Viszeral- und Transplantationschirurgie, Hellmut-Hartert-Straße 1, 67655, Kaiserslautern, Deutschland.
| |
Collapse
|
|
18
|
Jansen H, Pape UF, Utku N. A review of systemic therapy in biliary tract carcinoma. J Gastrointest Oncol 2020; 11:770-789. [PMID: 32953160 PMCID: PMC7475338 DOI: 10.21037/jgo-20-203] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Accepted: 07/13/2020] [Indexed: 12/11/2022] Open
Abstract
Biliary tract carcinoma (BTC) has a poor prognosis and is increasing in incidence. Although surgery, chemotherapy and other treatment modalities have improved, surgery remains the only potential curative treatment and is appropriate for only those few patients who present with localized, resectable disease. However, for the majority of patients, unresectable disease is evident at diagnosis and about 95% of patients die within 10 years, despite the majority receiving chemotherapy. Long-term survival is significantly greater for patients with resected BTC compared to those with unresectable disease. In unresected disease, life expectancy is limited, with first-line gemcitabine/cisplatin (GEM/CIS) accepted as standard of care. Currently no standard second-line regimen which provides significant improvement of clinical outcomes exists for those who present with refractory disease or who relapse after first-line treatment. Of particular importance is establishing the impact of best supportive care (BSC) as a benchmark for survival outcomes to which the impact of treatment modalities can be compared. Survival outcome often differs significantly for patients with different prognostic factor profiles even when receiving the same therapy so that it can be difficult to predict which patient subgroup might benefit most from which therapy. Therefore, the influence of prognostic factors on survival under different therapies as well as under BSC needs to be further assessed in order to arrive at truly evidence-based, best therapeutic decisions for individual patients. Encouraging new research into the genomic landscape of BTC may help to further subdivide the BTC population into molecular-genetic clusters likely to be sensitive to different targeted therapy approaches leading to further improvements in survival. Consequently, an unmet need exists not only to develop new and more effective therapies for this devastating disease, but also to integrate original research findings into a more complex, dynamic, individualized therapeutic decision model to aid clinicians in making evidence-based, best therapeutic decisions for individual patients.
Collapse
Affiliation(s)
- Holger Jansen
- Campus Virchow & Mitte Charité, Institute f. Med. Immunologie, Berlin, Germany
| | - Ulrich-Frank Pape
- Hepatology and Gastroenterology, Charité Universitätsmedizin Berlin, Germany
- Internal Medicine and Gastroenterology, Asklepios Klinik St. Georg, Asklepios Tumor Zentrum Hamburg, Germany
| | - Nalân Utku
- Campus Virchow & Mitte Charité, Institute f. Med. Immunologie, Berlin, Germany
- CellAct Pharma GmbH, Dortmund, Germany
| |
Collapse
|
|
19
|
Li J, Chen Q, Jin B, Shi Y, Wu X, Xu H, Zheng Y, Wang Y, Du S, Lu X, Mao Y, Sang X. Preoperative Bilirubin-Adjusted Carbohydrate Antigen 19-9 as a Prognostic Factor for Extrahepatic Cholangiocarcinoma Patients at a Single Center. Cancer Manag Res 2020; 12:411-417. [PMID: 32021453 PMCID: PMC6980863 DOI: 10.2147/cmar.s229329] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2019] [Accepted: 12/17/2019] [Indexed: 01/06/2023] Open
Abstract
Purpose The aims of our study were to investigate the prognostic impact of the rate of preoperative serum carbohydrate antigen 19-9/bilirubin (CA19-9/BR) on patients with extrahepatic bile duct cancer. Patients and Methods We collected clinical data from 89 patients who underwent surgery for extrahepatic cholangiocarcinoma (ECC) at Peking Union Medical College Hospital between January 2012 and December 2017. The Kaplan–Meier analysis for univariate analysis and the Cox proportional hazards models for multivariate analysis were used to determine possible independent prognostic factors. Results CA19-9/BR was classified as elevated compared with normal based on the upper serum normal values of CA19-9 (37 U/mL) and bilirubin (1.5 mg/dL), which gives a cut-off at 25 U/mL/mg/dL. Univariate analysis showed that the overall survival of patients with a high CA19-9/BR ratio was significantly worse compared with patients with a low CA19-9/BR ratio (Hazard Ratio [HR] 2.149; 95% Confidence Interval [95% CI] 1.027–4.495; P=0.042). Multivariate analysis revealed that a high CA19-9/BR ratio (HR 3.250; 95% CI 1.165–9.067; P=0.024), low differentiation (HR 3.551; 95% CI 1.231–10.244; P=0.019), and positive margin (HR 2.555; 95% CI 1.111–5.875; P=0.027) remained independent prognostic factors after adjusting for age at diagnosis, maximal diameters, and other possible factors. Conclusion The preoperative CA19-9/BR ratio is a good prognostic factor in predicting survival in ECC patients and closer follow-up is recommended in patients with a higher CA19-9/BR ratio before surgery.
Collapse
Affiliation(s)
- Jiayi Li
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, People's Republic of China
| | - Qiao Chen
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, People's Republic of China
| | - Bao Jin
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, People's Republic of China
| | - Yue Shi
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, People's Republic of China
| | - Xiangan Wu
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, People's Republic of China
| | - Haifeng Xu
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, People's Republic of China
| | - Yongchang Zheng
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, People's Republic of China
| | - Yingyi Wang
- Department of Oncology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, People's Republic of China
| | - Shunda Du
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, People's Republic of China
| | - Xin Lu
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, People's Republic of China
| | - Yilei Mao
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, People's Republic of China
| | - Xinting Sang
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, People's Republic of China
| |
Collapse
|
|
20
|
Huguet JM, Lobo M, Labrador JM, Boix C, Albert C, Ferrer-Barceló L, Durá AB, Suárez P, Iranzo I, Gil-Raga M, Burgos CBD, Sempere J. Diagnostic-therapeutic management of bile duct cancer. World J Clin Cases 2019; 7:1732-1752. [PMID: 31417920 PMCID: PMC6692271 DOI: 10.12998/wjcc.v7.i14.1732] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2019] [Revised: 06/18/2019] [Accepted: 06/26/2019] [Indexed: 02/05/2023] Open
Abstract
Biliary tract cancer, or cholangiocarcinoma, comprises a heterogeneous group of malignant tumors that can emerge at any part of the biliary tree. This group is the second most common type of primary liver cancer. Diagnosis is usually based on symptoms, which may be heterogeneous, and nonspecific biomarkers in serum and biopsy specimens, as well as on imaging techniques. Endoscopy-based diagnosis is essential, since it enables biopsy specimens to be taken. In addition, it can help with locoregional staging of distal tumors. Endoscopic retrograde cholangiopancreatography is a key technique for the evaluation and treatment of malignant biliary tumors. Correct staging of cholangiocarcinoma is essential in order to be able to determine the degree of resectability and assess the results of treatment. The tumor is staged based on the TNM classification of the American Joint Committee on Cancer. The approach will depend on the classification of the tumor. Thus, some patients with early-stage disease could benefit from surgery; complete surgical resection is the cornerstone of cure. However, only a minority of patients are diagnosed in the early stages and are suitable candidates for resection. In the subset of patients diagnosed with locally advanced or metastatic disease, chemotherapy has been used to improve outcome and to delay tumor progression. The approach to biliary tract tumors should be multidisciplinary, involving experienced endoscopists, oncologists, radiologists, and surgeons.
Collapse
Affiliation(s)
- José María Huguet
- Digestive Disease Department, General University Hospital of Valencia, Valencia 46014, Spain
| | - Miriam Lobo
- Medical Oncology Department, General University Hospital of Valencia, Valencia 46014, Spain
| | - José Mir Labrador
- Unidad Hepática Avanzada, Servicio de Cirugía General y Digestiva, General University Hospital of Valencia, Valencia 46014, Spain
| | - Carlos Boix
- Digestive Disease Department, General University Hospital of Valencia, Valencia 46014, Spain
| | - Cecilia Albert
- Digestive Disease Department, General University Hospital of Valencia, Valencia 46014, Spain
| | - Luis Ferrer-Barceló
- Digestive Disease Department, General University Hospital of Valencia, Valencia 46014, Spain
| | - Ana B Durá
- Digestive Disease Department, General University Hospital of Valencia, Valencia 46014, Spain
| | - Patricia Suárez
- Digestive Disease Department, General University Hospital of Valencia, Valencia 46014, Spain
| | - Isabel Iranzo
- Digestive Disease Department, General University Hospital of Valencia, Valencia 46014, Spain
| | - Mireia Gil-Raga
- Medical Oncology Department, Hospital de Requena, Requena 46340, Spain
| | - Celia Baez de Burgos
- Unidad Hepática Avanzada, Servicio de Cirugía General y Digestiva, General University Hospital of Valencia, Valencia 46014, Spain
| | | |
Collapse
|
|
21
|
Martin SP, Ruff S, Diggs LP, Drake J, Ayabe RI, Brown ZJ, Wach MM, Steinberg SM, Davis JL, Hernandez JM. Tumor grade and sex should influence the utilization of portal lymphadenectomy for early stage intrahepatic cholangiocarcinoma. HPB (Oxford) 2019; 21:419-424. [PMID: 30139566 PMCID: PMC8142509 DOI: 10.1016/j.hpb.2018.07.026] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2018] [Revised: 07/23/2018] [Accepted: 07/25/2018] [Indexed: 12/12/2022]
Abstract
BACKGROUND Portal lymphadenectomy for intrahepatic cholangiocarcinoma (ICC) is encouraged for staging purposes, though it is under-utilized for clinically early-stage tumors. We sought to determine if any factor knowable prior to resection influences rates of portal lymph node metastases. METHODS The Surveillance, Epidemiology, and End Results (SEER) Program (1973-2014) database was queried to identify patients with T1/T2 ICC undergoing resection. Patients were stratified by lymph node (LN) status. Patients deemed LN negative required examination of six or more LNs (AJCC guidelines). RESULTS One-hundred and fifty-two patients were included in the analysis (LN negative: 38, LN positive: 114). Patients with LN negative cancers experienced prolonged overall survival as compared to patients with positive LNs (median 77 months vs 19 months, respectively p < 0.001). Twelve patients had well-differentiated tumors (G1), 92 patients had moderately-differentiated tumors (G2) and 58 patients had poorly-differentiated tumors (G3). Tumor grade (OR 3.9, CI 1.1-13.7, p = 0.031) and male sex (OR 2.6, CI 1.1-6.1, p = 0.022) were associated with positive LNs on multivariable logistic regression analysis. CONCLUSION Intermediate/High grade and male sex are associated with high rates of lymph node metastasis for patients with early-stage ICC, which portends abbreviated overall survival.
Collapse
Affiliation(s)
- Sean P Martin
- Thoracic and Oncologic Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Building 10, Room 4-3942, Bethesda, MD, 20892, USA.
| | - Samantha Ruff
- Thoracic and Oncologic Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Building 10, Room 4-3942, Bethesda, MD, 20892, USA.
| | - Laurence P Diggs
- Thoracic and Oncologic Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Building 10, Room 4-3942, Bethesda, MD, 20892, USA.
| | - Justin Drake
- Thoracic and Oncologic Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Building 10, Room 4-3942, Bethesda, MD, 20892, USA.
| | - Reed I Ayabe
- Thoracic and Oncologic Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Building 10, Room 4-3942, Bethesda, MD, 20892, USA.
| | - Zachary J Brown
- Thoracic and Oncologic Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Building 10, Room 4-3942, Bethesda, MD, 20892, USA.
| | - Michael M Wach
- Thoracic and Oncologic Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Building 10, Room 4-3942, Bethesda, MD, 20892, USA.
| | - Seth M Steinberg
- Biostatistics and Data Management Section, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 9609 Medical Center Drive, Room 2W334, Rockville, MD, 20850, USA.
| | - Jeremy L Davis
- Thoracic and Oncologic Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Building 10, Room 4-3942, Bethesda, MD, 20892, USA.
| | - Jonathan M Hernandez
- Thoracic and Oncologic Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Building 10, Room 4-3942, Bethesda, MD, 20892, USA.
| |
Collapse
|
|
22
|
Martin SP, Drake J, Wach MM, Ruff S, Diggs LP, Wan JY, Brown ZJ, Ayabe RI, Glazer ES, Dickson PV, Davis JL, Deneve JL, Hernandez JM. Laparoscopic Approach to Intrahepatic Cholangiocarcinoma is Associated with an Exacerbation of Inadequate Nodal Staging. Ann Surg Oncol 2019; 26:1851-1857. [PMID: 30895496 DOI: 10.1245/s10434-019-07303-0] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2018] [Indexed: 02/06/2023]
Abstract
INTRODUCTION Laparoscopic approach to liver resection is feasible and safe, though its utilization with intrahepatic cholangiocarcinoma (ICC) remains poorly documented. We sought to evaluate the use laparoscopy for ICC, and to examine adherence to oncologic standards. METHODS The National Cancer Database was queried for patients who underwent resection for ICC. Patients were stratified by laparoscopic (LLR) versus open liver resection (OLR). Clinicopathologic parameters and hospital volumes were recorded. RESULTS In total, 2309 patients with ICC underwent hepatic resection (1997 OLR, 312 LLR) between 2010 and 2015. LLR increased from 12 to 16% during the study period and was utilized more commonly than OLR for wedge and segmental resections (56% vs. 33%, p < 0.001). Nodal evaluation was performed in 58% of all patients with ICC and was significantly more common in patients undergoing OLR (61%, n = 1210) versus LLR (39%, n = 120), p < 0.001. Of the 120 patients undergoing LLR with any nodal evaluation, 31% (n = 37) had a single node evaluated. Patients who underwent LLR were less likely to have ≥ 6 lymph nodes evaluated compared with those who underwent OLR (9% vs. 15%, respectively, p < 0.001). CONCLUSIONS The use of laparoscopy for ICC is associated with an exacerbation of inadequate nodal evaluation compared with open resections.
Collapse
Affiliation(s)
- Sean P Martin
- Surgical Oncology Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Justin Drake
- Surgical Oncology Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.,Division of Surgical Oncology, Department of Surgery, University of Tennessee Health Science Center, Memphis, TN, USA
| | - Michael M Wach
- Surgical Oncology Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Samantha Ruff
- Surgical Oncology Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Laurence P Diggs
- Surgical Oncology Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Jim Y Wan
- Division of Surgical Oncology, Department of Surgery, University of Tennessee Health Science Center, Memphis, TN, USA
| | - Zachary J Brown
- Surgical Oncology Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Reed I Ayabe
- Surgical Oncology Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Evan S Glazer
- Division of Surgical Oncology, Department of Surgery, University of Tennessee Health Science Center, Memphis, TN, USA
| | - Paxton V Dickson
- Division of Surgical Oncology, Department of Surgery, University of Tennessee Health Science Center, Memphis, TN, USA
| | - Jeremy L Davis
- Division of Surgical Oncology, Department of Surgery, University of Tennessee Health Science Center, Memphis, TN, USA
| | - Jeremiah L Deneve
- Division of Surgical Oncology, Department of Surgery, University of Tennessee Health Science Center, Memphis, TN, USA.
| | - Jonathan M Hernandez
- Surgical Oncology Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
| |
Collapse
|
|
23
|
Fu H, Dong R, Zhang Y, Xu J, Liu M, Chen P. Tmub1 negatively regulates liver regeneration via inhibiting STAT3 phosphorylation. Cell Signal 2019; 55:65-72. [PMID: 30610893 DOI: 10.1016/j.cellsig.2018.12.013] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2018] [Revised: 12/30/2018] [Accepted: 12/31/2018] [Indexed: 12/24/2022]
Abstract
Tmub1 (transmembrane and ubiquitin-like domain-containing 1) plays negative roles in rat hepatocyte proliferation, but its underlying molecular mechanisms in liver regeneration regulation have yet to be revealed. Here, we show that in vivo transfection of Tmub1 overexpression vectors impaired mouse liver regeneration after partial hepatectomy (PHx). Loss- and gain-of-function analyses in human hepatocyte Lo2 cells indicated that Tmub1 inhibits the phosphorylation of STAT3 and the activation of STAT3 signaling. Furthermore, the inhibitory effect of Tmub1 overexpression on hepatocyte proliferation can be reversed by the STAT3 activator OSM, while the promotive effect of Tmub1 knockdown can be abolished by the STAT3 inhibitor stattic. Coimmunoprecipitation assays revealed interaction between Tmub1 and STAT3. Finally, we present data from chromatin immunoprecipitation and luciferase reporter gene assays and report that STAT3 binds to and activates the promoter of Tmub1, suggesting a putative negative feedback loop between Tmub1 and STAT3 signaling. Taken together, the results of our study suggest that Tmub1 is an important negative regulator of hepatocyte proliferation in liver regeneration through STAT3 signaling. These findings provide a potential strategy for the management of liver regeneration.
Collapse
Affiliation(s)
- Hangwei Fu
- Department of Hepatobiliary Surgery, Daping Hospital (Army Medical Center), Third Military Medical University (Army Medical University), Chongqing 400042, China
| | - Rui Dong
- Department of Hepatobiliary Surgery, Daping Hospital (Army Medical Center), Third Military Medical University (Army Medical University), Chongqing 400042, China
| | - Yida Zhang
- Department of Hepatobiliary Surgery, Daping Hospital (Army Medical Center), Third Military Medical University (Army Medical University), Chongqing 400042, China
| | - Jianhua Xu
- Department of Hepatobiliary Surgery, Daping Hospital (Army Medical Center), Third Military Medical University (Army Medical University), Chongqing 400042, China
| | - Menggang Liu
- Department of Hepatobiliary Surgery, Daping Hospital (Army Medical Center), Third Military Medical University (Army Medical University), Chongqing 400042, China.
| | - Ping Chen
- Department of Hepatobiliary Surgery, Daping Hospital (Army Medical Center), Third Military Medical University (Army Medical University), Chongqing 400042, China.
| |
Collapse
|
|
24
|
Hester C, Nassour I, Adams-Huet B, Augustine M, Choti MA, Minter RM, Mansour JC, Polanco PM, Porembka MR, Wang SC, Yopp AC. Improved Survival in Surgically Resected Distal Cholangiocarcinoma Treated with Adjuvant Therapy: a Propensity Score Matched Analysis. J Gastrointest Surg 2018; 22:2080-2087. [PMID: 30030718 DOI: 10.1007/s11605-018-3875-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2018] [Accepted: 07/03/2018] [Indexed: 01/31/2023]
Abstract
BACKGROUND Data on the efficacy of adjuvant therapy (AT) in distal cholangiocarcinoma (dCCA) is limited. This study aimed to determine the role of AT in resected dCCA and identify subgroups that benefit from AT. METHODS We conducted a retrospective review of surgically resected dCCA in the NCDB from 2004 to 2013. Patients who received AT or observation (OB) were matched by propensity score. Log-rank test was used to compare OS. RESULTS Of 1782 patients with resected dCCA, 840 (47%) were in the OB group and 942 (53%) in the AT group. AT was younger (64.0 vs. 68.7 years, p < 0.001), had less comorbidities (Charlson Deyo score 0) (74.6 vs. 68.0%, p < 0.001), and more likely to have private insurance (p < 0.001). AT was more likely to present with T3/T4 stage (72 vs. 57%, p < 0.001), N1/N2 disease (58 vs. 37%, p < 0.001), and positive surgical margins (26 vs. 16%, p < 0.001). After 1:1 propensity score matching, 500 OB and 500 AT patients were compared. AT was associated with better OS (HR 0.79; 95% CI 0.67-0.93). Median OS was 31 and 25 months for the AT and OB (p = 0.006). The 1-, 3-, and 5-year survival rates were 87, 46, and 31% for AT; 79, 39, and 24% for OB. Subgroup analysis revealed an associated survival advantage for AT in T3/T4 tumors (HR = 0.72; 95% CI 0.59-0.89), node positive disease (HR 0.70; 95% CI 0.56-0.87), and positive margins (HR 0.58; 95% CI 0.42-0.81). CONCLUSION AT is associated with improved OS in resected dCCA, especially in T3/T4 tumors, node positive disease, and positive margins.
Collapse
Affiliation(s)
- Caitlin Hester
- Department of Surgery, Division of Surgical Oncology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX, 75390, USA
| | - Ibrahim Nassour
- Department of Surgery, Division of Surgical Oncology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX, 75390, USA
| | - Beverley Adams-Huet
- Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, USA
| | - Mathew Augustine
- Department of Surgery, Division of Surgical Oncology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX, 75390, USA
| | - Michael A Choti
- Department of Surgery, Division of Surgical Oncology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX, 75390, USA
| | - Rebecca M Minter
- Department of Surgery, Division of Surgical Oncology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX, 75390, USA
| | - John C Mansour
- Department of Surgery, Division of Surgical Oncology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX, 75390, USA
| | - Patricio M Polanco
- Department of Surgery, Division of Surgical Oncology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX, 75390, USA.,Department of Veterans Affairs North Texas Health Care System, Dallas, USA
| | - Matthew R Porembka
- Department of Surgery, Division of Surgical Oncology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX, 75390, USA
| | - Sam C Wang
- Department of Surgery, Division of Surgical Oncology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX, 75390, USA
| | - Adam C Yopp
- Department of Surgery, Division of Surgical Oncology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX, 75390, USA.
| |
Collapse
|
|
25
|
Manekeller S, Kalff JC. [Treatment approach for gall bladder and extrahepatic bile duct cancer]. Chirurg 2018; 89:880-886. [PMID: 30094707 DOI: 10.1007/s00104-018-0704-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
BACKGROUND Although the treatment and diagnostic regimens of gall bladder carcinoma and extrahepatic bile duct cancer have improved over the past years, the outcome and overall survival as prognostic values still remain poor. Early tumor stages of gall bladder carcinoma are the only exception. OBJECTIVE This article focuses on the latest surgical therapy approaches including neoadjuvant, adjuvant and palliative therapy regimens. RESULTS Neoadjuvant treatment concepts have so far been insufficiently evaluated and can therefore only be recommended within the framework of studies. In patients with primary resectable tumors there are so far no indications for improved results after neoadjuvant therapy. Radical R0 resection still remains the only curative treatment option; however, an advanced and inoperable stage is often already present at the time of diagnosis There are no uniform adjuvant treatment concepts and no standards evaluated by studies. Due to the currently available data, adjuvant radiochemotherapy and chemotherapy can also only be recommended within or as part of clinical trials. Palliative chemotherapy should only be used in advanced tumor stages and depending on the condition of the patient. CONCLUSION To sustainably improve treatment strategies for advanced gall bladder carcinoma and extrahepatic bile duct cancer, uniform adjuvant as well as neoadjuvant therapy regimens need to be developed after evaluation in prospective randomized trials. This is the only way to improve the still poor prognosis of these tumor entities.
Collapse
Affiliation(s)
- S Manekeller
- Klinik und Poliklinik für Allgemein‑, Viszeral‑, Thorax- und Gefäßchirurgie, Universitätsklinikum der Rheinischen Friedrich-Wilhelms-Universität Bonn, Sigmund-Freud-Straße 25, 53127, Bonn, Deutschland.
| | - J C Kalff
- Klinik und Poliklinik für Allgemein‑, Viszeral‑, Thorax- und Gefäßchirurgie, Universitätsklinikum der Rheinischen Friedrich-Wilhelms-Universität Bonn, Sigmund-Freud-Straße 25, 53127, Bonn, Deutschland
| |
Collapse
|
|
26
|
Pang Y, Hou X, Yang C, Liu Y, Jiang G. Advances on chimeric antigen receptor-modified T-cell therapy for oncotherapy. Mol Cancer 2018; 17:91. [PMID: 29769134 PMCID: PMC5956614 DOI: 10.1186/s12943-018-0840-y] [Citation(s) in RCA: 56] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2018] [Accepted: 05/02/2018] [Indexed: 02/06/2023] Open
Abstract
Tumor treatment is still complicated in the field of medicine. Tumor immunotherapy has been the most interesting research field in cancer therapy. Application of chimeric antigen receptor T (CAR-T) cell therapy has recently achieved excellent clinical outcome in patients, especially those with CD19-positive hematologic malignancies. This phenomenon has induced intense interest to develop CAR-T cell therapy for cancer, especially for solid tumors. However, the performance of CAR-T cell treatment in solid tumor is not as satisfactory as that in hematologic disease. Clinical studies on some neoplasms, such as glioblastoma, ovarian cancer, and cholangiocarcinoma, have achieved desirable outcome. This review describes the history and evolution of CAR-T, generalizes the structure and preparation of CAR-T, and summarizes the latest advances on CAR-T cell therapy in different tumor types. The last section presents the current challenges and prospects of CAR-T application to provide guidance for subsequent research.
Collapse
Affiliation(s)
- Yanyu Pang
- Department of Dermatology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221002, China
| | - Xiaoyang Hou
- Department of Dermatology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221002, China
| | - Chunsheng Yang
- Department of Dermatology, Affiliated Huai'an Hospital of Xuzhou Medical University, the Second People's Hospital of Huai'an, Huai'an, 223002, China
| | - Yanqun Liu
- Department of Dermatology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221002, China.
| | - Guan Jiang
- Department of Dermatology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221002, China.
| |
Collapse
|
|
27
|
Singsuksawat E, Thuwajit C, Charngkaew K, Thuwajit P. Increased ETV4 expression correlates with estrogen-enhanced proliferation and invasiveness of cholangiocarcinoma cells. Cancer Cell Int 2018; 18:25. [PMID: 29467595 PMCID: PMC5819217 DOI: 10.1186/s12935-018-0525-z] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2017] [Accepted: 02/16/2018] [Indexed: 12/19/2022] Open
Abstract
Background Cholangiocarcinoma (CCA) is one of the worst prognosis cancer. The survival time of CCA patients is related to serum estrogen levels and estrogen has been found to enhance the proliferation and invasiveness of CCA cells in vitro. This has led to the suggestion that estrogen may play an important role in the progression of CCA. This study tests the relevance of the previous in vitro findings in vivo using a mouse xenograft model of CCA, and investigates possible signaling mechanisms involved. Methods KKU-213 and KKU-139 CCA cell lines were used in the experiments, xenografted to nude mice and treated with a potent estrogenic agent, 17β-estradiol (E2), and/or with tamoxifen (TAM), an estrogen antagonist. Results The results demonstrated that E2 could accelerate growth of the xenograft-tumor and the effect was inhibited by TAM. PCR array screening of E2 responsive genes suggested ETV4 as a promising candidate intracellular mediator. ETV4-knockdown CCA cells were generated and these showed a diminished responsiveness to E2 in both cell and spheroid proliferation assays, and in invasion tests. These results point to ETV4 as a possible mediator of E2-activated CCA progression and as a potential target of TAM-mediated inhibition. Conclusions Finally, TAM may be suggested as an adjunctive treatment of CCA to improve the conventional cytotoxic method with more patient toleration. Electronic supplementary material The online version of this article (10.1186/s12935-018-0525-z) contains supplementary material, which is available to authorized users.
Collapse
Affiliation(s)
- Ekapot Singsuksawat
- 1Graduate Program in Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, 2 Wang Lang Road, Bangkok Noi, Bangkok, 10700 Thailand.,2Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, 2 Wang Lang Road, Bangkok Noi, Bangkok, 10700 Thailand
| | - Chanitra Thuwajit
- 2Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, 2 Wang Lang Road, Bangkok Noi, Bangkok, 10700 Thailand
| | - Komgrid Charngkaew
- 3Department of Pathology, Faculty of Medicine Siriraj Hospital, Mahidol University, 2 Wang Lang Road, Bangkok Noi, Bangkok, 10700 Thailand
| | - Peti Thuwajit
- 2Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, 2 Wang Lang Road, Bangkok Noi, Bangkok, 10700 Thailand.,4NANOTEC-Mahidol University Center of Excellence in Nanotechnology for Cancer Diagnosis and Treatment, Faculty of Medicine Siriraj Hospital, Mahidol University, 2 Wang Lang Road, Bangkok Noi, Bangkok, 10700 Thailand
| |
Collapse
|
|
28
|
Capobianco I, Rolinger J, Nadalin S. Resection for Klatskin tumors: technical complexities and results. Transl Gastroenterol Hepatol 2018; 3:69. [PMID: 30363698 PMCID: PMC6182019 DOI: 10.21037/tgh.2018.09.01] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2018] [Accepted: 08/27/2018] [Indexed: 12/18/2022] Open
Abstract
Klatskin's tumors, actually-redefined as perihilar cholangiocarcinoma (phCCA) do represent 50-70% of all CCAs and develop in a context of chronic inflammation and cholestasis of bile ducts. Surgical resection provides the only chance of cure for this disease but is technically challenging because of the complex, intimate and variable relationship between biliary and vascular structures at this location. Five years survival rates range between 25-45% (median 27-58 months) in case of R0 resection and 0-23% (median 12-21 months) in case of R1 resection respectively. It should be noted that the major costs of high radicality are represented by relative high morbidity and mortality rates (i.e., 20-66% and 0-9% respectively). Considering the fact that radical resection may represent the only curative treatment of phCCA, we focused our review on surgical planning and techniques that may improve resectability rates and outcomes for locally advanced phCCA. The surgical treatment of phCCA can be successful when following aspects have been fulfilled: (I) accurate preoperative diagnostic aimed to identify the tumor in all its details (localization and extension) and to study all the risk factors influencing a posthepatectomy liver failure (PHLF): i.e., liver volume, liver function, liver quality, haemodynamics and patient characteristics; (II) High end surgical skills taking in consideration the local extension of the tumor and the vascular invasion which usually require an extended hepatic resection and often a vascular resection; (III) adequate postoperative management aimed to avoid major complications (i.e., PHLF and biliary complications). These are technically challenging operations and must be performed in a high volume centres by hepato-biliary-pancreas (HBP)-surgeons with experience in microsurgical vascular techniques.
Collapse
Affiliation(s)
- Ivan Capobianco
- Department of General, Visceral and Transplant Surgery, University Hospital Tuebingen, Tuebingen, Germany
| | - Jens Rolinger
- Department of General, Visceral and Transplant Surgery, University Hospital Tuebingen, Tuebingen, Germany
| | - Silvio Nadalin
- Department of General, Visceral and Transplant Surgery, University Hospital Tuebingen, Tuebingen, Germany
| |
Collapse
|
|
29
|
Ryu J, Lee K, Joe C, Joo J, Lee N, Yoo HS. Patient With Unresectable Cholangiocarcinoma Treated With Radiofrequency Hyperthermia in Combination With Chemotherapy: A Case Report. Integr Cancer Ther 2017; 17:558-561. [PMID: 28745084 PMCID: PMC6041912 DOI: 10.1177/1534735417722225] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Hyperthermia, which is a noninvasive treatment that causes tumor cells to become heated and that works in synergy with anticancer drugs and radiation therapy, is emerging as a promising treatment for patients with cancer. The purpose of this study is to report the efficacy of hyperthermia combined with chemotherapy (gemcitabine/cisplatin) for the treatment of a patient with unresectable cholangiocarcinoma. A 54-year-old man was diagnosed as hilar cholangiocarcinoma (Klatskin tumor) and was administered neoadjuvant and preoperative radiation with chemotherapy. However, because the treatment with radiation and chemotherapy was not successful, he decided to undergo hyperthermia combined with chemotherapy as a second treatment option. He was suffering from fatigue, dyspepsia, epigastralgia, and jaundice. Hyperthermia combined with chemotherapy was administered 32 times over a period of 4 months. The patient experienced no critical complications, and the patient’s condition improved, with the carbohydrate antigen 19-9 (CA 19-9) and the total bilirubin levels being relatively lowered. In addition, the computed tomography scan showed that the cholangiocarcinoma had not progressed. In conclusion, this case report suggests radiofrequency hyperthermia combined with chemotherapy may be a promising treatment option for patients with unresectable cholangiocarcinoma.
Collapse
Affiliation(s)
- Juyoung Ryu
- 1 Cheonan Korean Medical Hospital, Daejeon University, Cheonan, Korea
| | - Kangwook Lee
- 1 Cheonan Korean Medical Hospital, Daejeon University, Cheonan, Korea
| | - Changmug Joe
- 1 Cheonan Korean Medical Hospital, Daejeon University, Cheonan, Korea
| | - JongCheon Joo
- 2 Jeonju Korean Medicine Hospital, Wonkwang University, Jeonju, Korea
| | - Namhun Lee
- 1 Cheonan Korean Medical Hospital, Daejeon University, Cheonan, Korea
| | - Hwa-Seung Yoo
- 3 Dunsan Korean Medicine Hospital, Daejeon University, Daejeon, Korea
| |
Collapse
|