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Peyle M, Massoud M, Patrier S, Gaillot-Durand L, Side G, Devouassoux-Shisheboran M, Massardier J, Descargues P, Msika A, Hajri T, Rousset P, Haesebaert J, Lotz JP, Jamelot M, You B, Golfier F, Eiriksson L, Allias F, Bolze PA. Impact of molecular genotyping on the diagnosis and treatment of human chorionic gonadotropin-producing tumors. J Gynecol Obstet Hum Reprod 2024; 53:102704. [PMID: 38040333 DOI: 10.1016/j.jogoh.2023.102704] [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] [Received: 09/05/2023] [Revised: 11/19/2023] [Accepted: 11/23/2023] [Indexed: 12/03/2023]
Abstract
OBJECTIVES To assess the use of molecular genotyping to accurately diagnose and treat human chorionic gonadotropin (hCG)-producing tumors and to evaluate the discriminating capacity of molecular testing on prognosis and overall survival. METHODS We conducted a retrospective descriptive study of patients registered with the French Reference Center for Trophoblastic Disease between 1999 and 2021. We included all patients with hCG-producing tumors for whom results of molecular genotyping were available. RESULTS Fifty-five patients with molecular genotyping were included: 81.2 % (n = 45) had tumors of gestational origin, 12.7 % (n = 7) of non-gestational origin and 5.5 % (n = 3) of undetermined origin. The results of molecular genotyping influenced the treatment decisions for 17 % of patients in this cohort. Overall survival was 93.3 % for patients with gestational tumors (after a median follow-up of 74 months) compared to 71.4 % for patients with non-gestational tumors (after a median follow-up of 23 months). CONCLUSION In atypical presentations of hCG-producing tumors, molecular genotyping is a valuable tool to guide diagnosis and tailor treatment recommendations.
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Affiliation(s)
- M Peyle
- Centre Français de Référence des Maladies Trophoblastiques, Hospices Civils de Lyon, Hôpital Lyon Sud, 69495 Pierre Bénite, France; Service de Chirurgie Gynécologique et Oncologique, Obstétrique, Hospices Civils de Lyon, Hôpital Lyon Sud, 69495 Pierre Bénite, France
| | - M Massoud
- Centre Français de Référence des Maladies Trophoblastiques, Hospices Civils de Lyon, Hôpital Lyon Sud, 69495 Pierre Bénite, France; Service de Chirurgie Gynécologique et Oncologique, Obstétrique, Hospices Civils de Lyon, Hôpital Lyon Sud, 69495 Pierre Bénite, France
| | - S Patrier
- Centre Français de Référence des Maladies Trophoblastiques, Hospices Civils de Lyon, Hôpital Lyon Sud, 69495 Pierre Bénite, France; Service d'anatomie et cytologie pathologique, Centre Hospitalier Universitaire de Rouen, 76000, Rouen, France
| | - L Gaillot-Durand
- Centre Français de Référence des Maladies Trophoblastiques, Hospices Civils de Lyon, Hôpital Lyon Sud, 69495 Pierre Bénite, France; Service de Pathologie - Hospices Civils de Lyon, Hôpital Lyon Sud, 69495 Pierre Bénite, France
| | - G Side
- Centre Français de Référence des Maladies Trophoblastiques, Hospices Civils de Lyon, Hôpital Lyon Sud, 69495 Pierre Bénite, France; Service d'anatomie et cytologie pathologique, Centre Hospitalier Universitaire de Rouen, 76000, Rouen, France
| | - M Devouassoux-Shisheboran
- Centre Français de Référence des Maladies Trophoblastiques, Hospices Civils de Lyon, Hôpital Lyon Sud, 69495 Pierre Bénite, France; Service de Pathologie - Hospices Civils de Lyon, Hôpital Lyon Sud, 69495 Pierre Bénite, France
| | - J Massardier
- Centre Français de Référence des Maladies Trophoblastiques, Hospices Civils de Lyon, Hôpital Lyon Sud, 69495 Pierre Bénite, France; Service de Gynécologie Obstétrique, Unité de Diagnostic Anténatal, Hôpital Femme Mère Enfant, Hospices Civils de Lyon, 59 boulevard Pinel, 69500 Bron, France
| | - P Descargues
- Centre Français de Référence des Maladies Trophoblastiques, Hospices Civils de Lyon, Hôpital Lyon Sud, 69495 Pierre Bénite, France; Service de Chirurgie Gynécologique et Oncologique, Obstétrique, Hospices Civils de Lyon, Hôpital Lyon Sud, 69495 Pierre Bénite, France
| | - A Msika
- Centre Français de Référence des Maladies Trophoblastiques, Hospices Civils de Lyon, Hôpital Lyon Sud, 69495 Pierre Bénite, France; Service de Chirurgie Gynécologique et Oncologique, Obstétrique, Hospices Civils de Lyon, Hôpital Lyon Sud, 69495 Pierre Bénite, France
| | - T Hajri
- Centre Français de Référence des Maladies Trophoblastiques, Hospices Civils de Lyon, Hôpital Lyon Sud, 69495 Pierre Bénite, France; Service de Chirurgie Gynécologique et Oncologique, Obstétrique, Hospices Civils de Lyon, Hôpital Lyon Sud, 69495 Pierre Bénite, France
| | - P Rousset
- Centre Français de Référence des Maladies Trophoblastiques, Hospices Civils de Lyon, Hôpital Lyon Sud, 69495 Pierre Bénite, France; Radiologie, Hôpital Lyon Sud, Hospices Civils de Lyon, 165, Chemin du Grand Revoyet, 69495 Pierre-Bénite, France; Université Lyon 1, Centre pour l'Innovation en Cancérologie de Lyon (CICLY), EA3738, Faculté de Médecine Lyon Sud Charles Mérieux, France
| | - J Haesebaert
- Centre Français de Référence des Maladies Trophoblastiques, Hospices Civils de Lyon, Hôpital Lyon Sud, 69495 Pierre Bénite, France; Pôle de Santé Publique, service de recherche et d'épidémiologie cliniques, Hospices Civils de Lyon, Lyon, France; Université Claude Bernard Lyon 1, U1290 Reshape, Lyon, France
| | - J P Lotz
- Centre Français de Référence des Maladies Trophoblastiques, Hospices Civils de Lyon, Hôpital Lyon Sud, 69495 Pierre Bénite, France; Hôpital Tenon, Pôle Onco-Hématologie Hôpitaux Universitaires de l'Est Parisien, Assistance Publique-Hôpitaux de Paris, 4 Rue de la Chine, 75020 Paris, France; Sorbonne Université, Faculté de Médecine, 91-105 Bd de l'Hôpital, 75013 Paris, France
| | - M Jamelot
- Centre Français de Référence des Maladies Trophoblastiques, Hospices Civils de Lyon, Hôpital Lyon Sud, 69495 Pierre Bénite, France; Hôpital Tenon, Pôle Onco-Hématologie Hôpitaux Universitaires de l'Est Parisien, Assistance Publique-Hôpitaux de Paris, 4 Rue de la Chine, 75020 Paris, France; Sorbonne Université, Faculté de Médecine, 91-105 Bd de l'Hôpital, 75013 Paris, France
| | - B You
- Centre Français de Référence des Maladies Trophoblastiques, Hospices Civils de Lyon, Hôpital Lyon Sud, 69495 Pierre Bénite, France; Université Lyon 1, Centre pour l'Innovation en Cancérologie de Lyon (CICLY), EA3738, Faculté de Médecine Lyon Sud Charles Mérieux, France; Service d'oncologie médicale, Institut de Cancérologie des Hospices Civils de Lyon (IC-HCL), CITOHL EPSILYON, Hospices Civils de Lyon, 69495 Pierre-Bénite, France
| | - F Golfier
- Centre Français de Référence des Maladies Trophoblastiques, Hospices Civils de Lyon, Hôpital Lyon Sud, 69495 Pierre Bénite, France; Service de Chirurgie Gynécologique et Oncologique, Obstétrique, Hospices Civils de Lyon, Hôpital Lyon Sud, 69495 Pierre Bénite, France; Université Lyon 1, Centre pour l'Innovation en Cancérologie de Lyon (CICLY), EA3738, Faculté de Médecine Lyon Sud Charles Mérieux, France
| | - L Eiriksson
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, McMaster University, Hamilton, ON, Canada; Department of Surgery, McMaster University, Hamilton, Ontario, Canada
| | - F Allias
- Centre Français de Référence des Maladies Trophoblastiques, Hospices Civils de Lyon, Hôpital Lyon Sud, 69495 Pierre Bénite, France; Service de Pathologie - Hospices Civils de Lyon, Hôpital Lyon Sud, 69495 Pierre Bénite, France
| | - P A Bolze
- Centre Français de Référence des Maladies Trophoblastiques, Hospices Civils de Lyon, Hôpital Lyon Sud, 69495 Pierre Bénite, France; Service de Chirurgie Gynécologique et Oncologique, Obstétrique, Hospices Civils de Lyon, Hôpital Lyon Sud, 69495 Pierre Bénite, France; Université Lyon 1, Centre pour l'Innovation en Cancérologie de Lyon (CICLY), EA3738, Faculté de Médecine Lyon Sud Charles Mérieux, France.
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Liu Y, Shi L, Chen K, Ye W. Identification and validation of serum tumor-markers based nomogram to predict the prognostic value of patients with cervical adenocarcinoma. Curr Probl Cancer 2022; 46:100899. [PMID: 36270166 DOI: 10.1016/j.currproblcancer.2022.100899] [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: 07/14/2022] [Revised: 08/30/2022] [Accepted: 09/14/2022] [Indexed: 01/30/2023]
Abstract
Unlike cervical squamous cell carcinoma (CSCC), no uniform standard has been implemented to identify serum biomarkers for adenocarcinoma of the cervix (ADC). In the present study, we aimed to determine whether pretreatment serum tumor markers were of prognostic value in patients with ADC and constructed and validated the novel accurate nomogram for stratifying the risk groups. Patients with ADC who underwent curative hysterectomy or definitive radiotherapy from January 2011 to December 2016 were included. Significant factors independently predicting prognosis were selected by univariate multivariate Cox proportional hazard regression models and adopted for constructing the overall survival (OS) and progression-free survival (PFS) prediction nomograms. The receiver operating characteristic (ROC) curve and concordance index (C-index) with calibration curve was used to determine the accuracy of the nomogram in the prediction and determination of performance. We enrolled a total of 295 samples and randomized them as the training set (n = 207) or validation set (n = 88). Federation of Gynecology and Obstetrics Staging Guidelines (FIGO) stage, para-aortic lymph node (PALN), carcinoembryonic antigen (CEA), neuron-specific enolase (NSE), and HCG-β were assessed as the common factors independently predicting OS and PFS. For our constructed nomograms, its C-index values in OS and PFS prediction were 0.896 (95% CI, 0.879-0.913) and 0.895 (95% CI, 0.878-0.912) in training set, whereas 0.845 (95% CI:0.796-0.894) and 0.846 (95% CI:0.797-0.895) in validation set. ROC and calibration curves for our constructed nomograms predicted the excellent consistency of nomogram-predicted values with real measurements of 1-, 3-, and 5-year OS. We explored novel prognostic serum tumor markers of ADC and constructed effective nomograms comprising NSE, HCG-β, FIGO stage, PALN, and CEA, which could estimate OS and PFS for patients with ADC. These nomograms performed well in predicting patient prognosis, which was a potentially useful approach for stratifying ADC risk, thus contributing to clinical decision-making and individualized follow-up planning.
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Affiliation(s)
- Yuxin Liu
- Department of Radiation Oncology, Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, People's Republic of China
| | - Liu Shi
- Department of Radiation Oncology, Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, People's Republic of China
| | - Kai Chen
- Department of Radiation Oncology, Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, People's Republic of China
| | - Weijun Ye
- Department of Radiation Oncology, Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, People's Republic of China.
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He M, Wang X, Xu J, Li J, Chang X, Zins M, Jin Z, Xue H. Diffuse Involvement of Pancreas is not Always Autoimmune Pancreatitis. Acad Radiol 2022; 29:1523-1531. [PMID: 35279380 DOI: 10.1016/j.acra.2022.01.013] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2021] [Revised: 01/09/2022] [Accepted: 01/16/2022] [Indexed: 02/07/2023]
Abstract
RATIONALE AND OBJECTIVES To determine the prevalence of diffuse involvement of pancreas and to identify the findings of malignancies using enhancement computed tomography (CT). MATERIALS AND METHODS A total of 1,0249 patients performed enhancement CT in our hospital over 62 months were investigated and the final study cohort includes 245 patients (170 males, 75 females; mean age, 56.94 ± 12.17 years). The reference standard is the final clinical/pathological diagnosis. The lesion-to-aorta enhancement ratio (LAR) on the pancreatic arterial phase, portal phase and delayed phase (DP) and the traditional CT findings were evaluated. Intergroup comparisons between malignancies and non-malignancies lesions were performed. Univariate and multivariate analyses were conducted to identify findings predicting malignancies. RESULTS The prevalence of malignancy was 45.3% (111/245) of diffuse enlargement of pancreas. All benign lesions were autoimmune pancreatitis 54.7% (n = 134). The most common malignant lesion was pancreatic ductal adenocarcinoma (n = 88, 35.9%). Other rare lesions with malignant potential included pancreatic neuroendocrine tumor (n = 11, 4.5%), lymphoma (n = 4, 1.6%), metastasis (n = 4, 1.6%), solid pseudopapillary neoplasm (n = 3, 1.2%) and acinar cell carcinoma (n = 1, 0.4%). Residual normal pancreas parenchyma, heterogeneity, short axis (cut-off value, 3.15 cm) and LARDP (cut-off value, 0.75) were independent predictors of malignancies. When the above predictors were combined, a sensitivity of 94.2%, a specificity of 90.8% were attained. CONCLUSION Diffuse involvement of the pancreas is rare and is not a specific sign of autoimmune pancreatitis, and it is associated with a wide spectrum of malignant conditions. Dynamic enhancement CT is helpful to identifying malignancies.
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Affiliation(s)
- Ming He
- Department of Radiology, Guangdong Provincial People's Hospital & Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, People's Republic of China; Department of Radiology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shuaifuyuan No.1, Dongcheng District, Beijing 100703, China
| | - Xiheng Wang
- Department of Radiology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shuaifuyuan No.1, Dongcheng District, Beijing 100703, China
| | - Jin Xu
- Department of Radiology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shuaifuyuan No.1, Dongcheng District, Beijing 100703, China
| | - Juan Li
- Department of Radiology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shuaifuyuan No.1, Dongcheng District, Beijing 100703, China
| | - Xiaoyan Chang
- Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Marc Zins
- Department of Rathology, Groupe Hospitalier Paris Saint Joseph, Paris, France
| | - Zhengyu Jin
- Department of Radiology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shuaifuyuan No.1, Dongcheng District, Beijing 100703, China
| | - Huadan Xue
- Department of Radiology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shuaifuyuan No.1, Dongcheng District, Beijing 100703, China.
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Gupta N, Yelamanchi R. Pancreatic adenocarcinoma: A review of recent paradigms and advances in epidemiology, clinical diagnosis and management. World J Gastroenterol 2021; 27:3158-3181. [PMID: 34163104 PMCID: PMC8218366 DOI: 10.3748/wjg.v27.i23.3158] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Revised: 03/03/2021] [Accepted: 05/21/2021] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer is one of the dreaded malignancies for both the patient and the clinician. The five-year survival rate of pancreatic adenocarcinoma (PDA) is as low as 2% despite multimodality treatment even in the best hands. As per the Global Cancer Observatory of the International Agency for Research in Cancer estimates of pancreatic cancer, by 2040, a 61.7% increase is expected in the total number of cases globally. With the widespread availability of next-generation sequencing, the entire genome of the tumors is being sequenced regularly, providing insight into their pathogenesis. As invasive PDA arises from pancreatic intraepithelial neoplasia and mucinous neoplasm and intraductal papillary neoplasm, screening for them can be beneficial as the disease is curable with resection at an early stage. Routine preoperative biliary drainage has no role in patients suffering from PDA with obstructive jaundice. If performed, metallic stents are preferred over plastic ones. Minimally invasive procedures are preferred to open procedures as they have less morbidity. The duct-to-mucosa technique for pancreaticojejunostomy is presently widely practiced. The role of intraperitoneal drains after surgery for PDA is controversial. Neoadjuvant chemoradiotherapy has been proven to have a significant role both in locally advanced as well as in resectable PDA. Many new regimens and drugs have been added in the arsenal of chemoradiotherapy for metastatic disease. The roles of immunotherapy and gene therapy in PDA are being investigated. This review article is intended to improve the understanding of the readers with respect to the latest updates of PDA, which may help to trigger new research ideas and make better management decisions.
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Affiliation(s)
- Nikhil Gupta
- Department of Surgery, Atal Bihari Vajpayee Institute of Medical Sciences and Dr. Ram Manohar Lohia Hospital, Delhi 110001, India
| | - Raghav Yelamanchi
- Department of Surgery, Atal Bihari Vajpayee Institute of Medical Sciences and Dr. Ram Manohar Lohia Hospital, Delhi 110001, India
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Andruska N, Mahapatra L, Brenneman R, MacArthur KM, Oppelt P, Baumann BC. False-positive pregnancy test secondary to ectopic expression of human chorionic gonadotropin by a gastrointestinal stromal tumor. J Surg Oncol 2020; 122:809-812. [PMID: 32615029 DOI: 10.1002/jso.26067] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2020] [Revised: 05/28/2020] [Accepted: 05/30/2020] [Indexed: 01/17/2023]
Abstract
Tumors can rarely overexpress human chorionic gonadotropin (hCG) resulting in false-positive pregnancy tests. Here, we report a 44-year-old female with a metastatic gastrointestinal stromal tumor (GIST) who presented with a positive urine pregnancy test before radiotherapy. Further workup ruled out pregnancy. Following radiotherapy, her metastatic disease progressed and her hCG level continued to rise. To the best of our knowledge, this is the first report of a GIST tumor overexpressing hCG.
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Affiliation(s)
- Neal Andruska
- Department of Radiation Oncology, Washington University School of Medicine, St. Louis, Missouri
| | - Lily Mahapatra
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri
| | - Randall Brenneman
- Department of Radiation Oncology, Washington University School of Medicine, St. Louis, Missouri
| | - Kelly M MacArthur
- Department of Dermatology, Washington University School of Medicine, St. Louis, Missouri
| | - Peter Oppelt
- Division of Medical Oncology, Washington University School of Medicine, St. Louis, Missouri
| | - Brian C Baumann
- Department of Radiation Oncology, Washington University School of Medicine, St. Louis, Missouri
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Kang S, Zaidi AJ, Shokouh-Amiri M, Wiley E, Venepalli NK. A case report of paraneoplastic syndrome in β-hCG-secreting duodenal adenocarcinoma. J Gastrointest Oncol 2019; 10:1151-1156. [PMID: 31949933 DOI: 10.21037/jgo.2019.09.08] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Human chorionic gonadotropin (hCG) is a glycoprotein hormone that is used in clinical practice to detect pregnancy and serves as a sensitive marker for trophoblastic tumors. Other organs besides placental trophoblasts naturally express the hormone at low levels, which can be elevated in nontrophoblastic malignancies. Some studies have suggested that elevated β-hCG levels in nontrophoblastic tumors are a sign of aggressive disease and strongly associated with poor prognosis. We describe a case of a 50-year-old post-menopausal woman with metastatic duodenal adenocarcinoma who presented with a negative pregnancy test that later changed to positive. Biopsy of the primary duodenal mass showed positive immunohistochemical expression of β-hCG. The patient was also found to have multiple brain metastases, which is uncommon in gastrointestinal cancer. This is a rare case of paraneoplastic syndrome in a β-hCG-secreting duodenal adenocarcinoma.
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Affiliation(s)
- Sandra Kang
- Division of Internal Medicine, University of Illinois at Chicago, Chicago, IL, USA
| | - Ayesha J Zaidi
- Oncology Clinical Trials Office, University of Illinois at Chicago, Chicago, IL, USA
| | | | - Elizabeth Wiley
- Department of Pathology, University of Illinois at Chicago, Chicago, IL, USA
| | - Neeta K Venepalli
- Division of Hematology Oncology, Department of Medicine Oncology, University of Illinois at Chicago, Chicago, IL, USA
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Zhang Y, Zhang M, Bai X, Li C, Zhang L. Increased serum CA724 levels in patients suffering gout vs cancers. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2019; 162:177-186. [PMID: 30905448 DOI: 10.1016/bs.pmbts.2018.12.005] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
CA724 is a clinically used serum biomarker used for cancer diagnosis, which includes digestive tract cancers (esophageal, gastric, and colorectal carcinomas), ovarian cancer, and nonsmall cell lung cancer. In general, the serum CA724 level is lower than 6U/mL in healthy controls and significantly higher in cancer patients. It has been further established that serum CA724 level is related to the pathological stage and prognosis of cancers. However, CA724 is not only expressed in tumor tissues but also in normal tissues such as the secretory endometrium and transitional colonic mucosa, which indicates that CA724 is not a unique product of cancer cells. Currently, the serum CA724 levels in patients suffering cancer or nonneoplasm diseases have not been systematically measured and compared. In our study, a total of 38,526 clinical lab test results of serum CA724 levels from healthy controls and patients suffering 34 different types of diseases including cancers and nonneoplasm illnesses during the past 3 years (2015-2018) were collected and analyzed. We found that the mean values of serum CA724 levels were significantly higher in patients suffering gout (23.7U/mL) and gouty arthritis (31.45U/mL) than that of cancer patients (Mann-Whitney test, p<0.0001). The summarized mean and median values of serum CA724 data for healthy controls vs patients suffering 34 different types of diseases indicated that the abnormal serum CA724 levels might be a systemic malfunction indicator rather than a cancer cell-secreted product; the log10p values showed that CA724 is not only a cancer biomarker but also a potential biomarker for patients suffering gout.
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Affiliation(s)
- Yiran Zhang
- Systems Biology and Medicine Center for Complex Diseases, Affiliated Hospital of Qingdao University, Qingdao, China.
| | - Meng Zhang
- Systems Biology and Medicine Center for Complex Diseases, Affiliated Hospital of Qingdao University, Qingdao, China
| | - Xueshan Bai
- Shandong Provincial Key Laboratory of Metabolic Disease, Affiliated Hospital of Qingdao University, Qingdao, China; China Shandong Gout Clinical Medical Center, Affiliated Hospital of Qingdao University, Qingdao, China
| | - Changgui Li
- Shandong Provincial Key Laboratory of Metabolic Disease, Affiliated Hospital of Qingdao University, Qingdao, China; China Shandong Gout Clinical Medical Center, Affiliated Hospital of Qingdao University, Qingdao, China
| | - Lijuan Zhang
- Systems Biology and Medicine Center for Complex Diseases, Affiliated Hospital of Qingdao University, Qingdao, China.
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Konishi Y, Kawamata F, Nishihara H, Homma S, Kato Y, Tsuda M, Kohsaka S, Einama T, Liu C, Yoshida T, Nagatsu A, Tanino M, Tanaka S, Kawamura H, Kamiyama T, Taketomi A. Tumor budding and human chorionic gonadotropin-β expression correlate with unfavorable patient outcome in colorectal carcinoma. Med Oncol 2018; 35:104. [PMID: 29892782 DOI: 10.1007/s12032-018-1164-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2018] [Accepted: 06/07/2018] [Indexed: 02/08/2023]
Abstract
Tumor budding is thought to represent a manifestation of epithelial-to-mesenchymal transition (EMT) and it has been correlated with poor patient outcomes in colorectal cancer (CRC). Our group recently demonstrated that human chorionic gonadotropin-β (hCGβ) modulates EMT in CRC. In the current study, based on the likely relationships between tumor budding and hCGβ expression, we examined their clinicopathologic significance in CRC. Twenty-eight of 80 (35.0%) CRC showed tumor budding. Tumor budding significantly correlated with lymph node metastasis (P < 0.01), pathologic stage (P < 0.01), lymphatic invasion (P = 0.044), and vascular invasion (P = 0.013). Thirteen of 80 (16.3%) CRC were hCGβ positive on immunohistochemistry. More tumor buds were present in the hCGβ-positive cases (P < 0.01), and tumor budding was significantly correlated with hCGβ positivity (P < 0.01). Cases with both tumor budding and hCGβ expression had the poorest prognosis compared with all other groups (P < 0.01). In conclusion, tumor budding and hCGβ expression are closely associated with EMT, and they are independent prognostic factors in CRC. They identify patients with an "EMT phenotype" who may respond to targeted molecular therapies.
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Affiliation(s)
- Yuji Konishi
- Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Kita-ku, Kita 14, Nishi 7, Sapporo, 060-8638, Japan
| | - Futoshi Kawamata
- Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Kita-ku, Kita 14, Nishi 7, Sapporo, 060-8638, Japan.
| | - Hiroshi Nishihara
- Genomics Unit, Keio Cancer Center, Keio University School of Medicine, Tokyo, Japan
| | - Shigenori Homma
- Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Kita-ku, Kita 14, Nishi 7, Sapporo, 060-8638, Japan
| | - Yasutaka Kato
- Genomics Unit, Keio Cancer Center, Keio University School of Medicine, Tokyo, Japan
| | - Masumi Tsuda
- Department of Cancer Pathology, Hokkaido University Graduate School of Medicine, Sapporo, Japan
| | - Shinji Kohsaka
- Department of Cellular Signaling, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
| | - Takahiro Einama
- Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Kita-ku, Kita 14, Nishi 7, Sapporo, 060-8638, Japan
| | - Cheng Liu
- Conjoint Gastroenterology Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Australia
| | - Tadashi Yoshida
- Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Kita-ku, Kita 14, Nishi 7, Sapporo, 060-8638, Japan
| | - Akihisa Nagatsu
- Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Kita-ku, Kita 14, Nishi 7, Sapporo, 060-8638, Japan
| | - Mishie Tanino
- Department of Cancer Pathology, Hokkaido University Graduate School of Medicine, Sapporo, Japan
| | - Shinya Tanaka
- Department of Cancer Pathology, Hokkaido University Graduate School of Medicine, Sapporo, Japan
| | - Hideki Kawamura
- Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Kita-ku, Kita 14, Nishi 7, Sapporo, 060-8638, Japan
| | - Toshiya Kamiyama
- Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Kita-ku, Kita 14, Nishi 7, Sapporo, 060-8638, Japan
| | - Akinobu Taketomi
- Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Kita-ku, Kita 14, Nishi 7, Sapporo, 060-8638, Japan
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Balmaña M, Duran A, Gomes C, Llop E, López-Martos R, Ortiz MR, Barrabés S, Reis CA, Peracaula R. Analysis of sialyl-Lewis x on MUC5AC and MUC1 mucins in pancreatic cancer tissues. Int J Biol Macromol 2018; 112:33-45. [PMID: 29408556 DOI: 10.1016/j.ijbiomac.2018.01.148] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2017] [Revised: 01/18/2018] [Accepted: 01/21/2018] [Indexed: 12/15/2022]
Abstract
Pancreatic adenocarcinoma (PDAC) lacks efficient biomarkers. Mucins are glycoproteins that can carry aberrant glycosylation in cancer. Our objective was to identify cancer-related glycan epitopes on MUC1 and MUC5AC mucins in PDAC as potential biomarkers. We have analysed the tumour-associated carbohydrate antigens sialyl-Lewis x (SLex) and sialyl-Tn (STn) on MUC1 and MUC5AC in PDAC tissues. The selected cohort for this study consisted of twenty-one PDAC tissues positive for SLex antigen and three normal pancreas specimens as controls. STn expression was shown in 76% of the PDAC tissues. MUC1 and MUC5AC were detected in 90% of PDAC tissues. We performed in situ proximity ligation assay combining antibodies against mucins and glycan epitopes to identify specific mucin glycoforms. MUC1-SLex and MUC5AC-SLex were found in 68% and 84% respectively, of the mucin expressing PDAC tissues, while STn hardly colocalized with any of the evaluated mucins. Further analysis by Western blot of MUC5AC and SLex in eight PDAC tissue lysates showed that six out of eight cases were positive for both markers. Moreover, immunoprecipitation of MUC5AC from positive PDAC tissues and subsequent SLex immunodetection confirmed the presence of SLex on MUC5AC. Altogether, MUC5AC-SLex glycoform is present in PDAC and can be regarded as potential biomarker.
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Affiliation(s)
- Meritxell Balmaña
- Biochemistry and Molecular Biology Unit, Department of Biology, University of Girona, Girona, Spain; Instituto de Investigação e Inovação em Saúde, I3S, Institute of Molecular Pathology and Immunology of University of Porto, Ipatimup, Porto, Portugal
| | - Adrià Duran
- Biochemistry and Molecular Biology Unit, Department of Biology, University of Girona, Girona, Spain
| | - Catarina Gomes
- Instituto de Investigação e Inovação em Saúde, I3S, Institute of Molecular Pathology and Immunology of University of Porto, Ipatimup, Porto, Portugal
| | - Esther Llop
- Biochemistry and Molecular Biology Unit, Department of Biology, University of Girona, Girona, Spain
| | - Raquel López-Martos
- Department of Anatomic Pathology, Dr. Trueta University Hospital, Girona, Spain
| | - M Rosa Ortiz
- Department of Anatomic Pathology, Dr. Trueta University Hospital, Girona, Spain
| | - Sílvia Barrabés
- Biochemistry and Molecular Biology Unit, Department of Biology, University of Girona, Girona, Spain
| | - Celso A Reis
- Instituto de Investigação e Inovação em Saúde, I3S, Institute of Molecular Pathology and Immunology of University of Porto, Ipatimup, Porto, Portugal; Medical Faculty, University of Porto, Al. Prof. Hernâni Monteiro, 4200-319 Porto, Portugal; Instituto de Ciências Biomédicas de Abel Salazar - ICBAS, University of Porto, Porto, Portugal.
| | - Rosa Peracaula
- Biochemistry and Molecular Biology Unit, Department of Biology, University of Girona, Girona, Spain.
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10
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Chorionic Gonadotropin-β Modulates Epithelial-Mesenchymal Transition in Colorectal Carcinoma Metastasis. THE AMERICAN JOURNAL OF PATHOLOGY 2017; 188:204-215. [PMID: 29037859 DOI: 10.1016/j.ajpath.2017.08.034] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/16/2017] [Revised: 08/15/2017] [Accepted: 08/28/2017] [Indexed: 12/12/2022]
Abstract
Ectopic production of free β human chorionic gonadotropin (hCGβ) has been associated with aggressive behavior in non-trophoblastic tumors. hCGβ shares common evolutionary sequences with transforming growth factor-β (TGF-β), which represents a major driving force of epithelial-to-mesenchymal transition (EMT). In this study, we examined the biological roles of hCGβ during EMT and its clinical significance in colorectal cancer (CRC) progression. Eighty CRC specimens and 54 preoperative serum samples were analyzed. hCGβ-overexpressing human CRC cell lines were examined for invasiveness and tumorigenicity, and the expression of EMT-associated genes was investigated. In human CRC, histologic hCGβ positivity [13/80 (16.3%)] was lower than serologic hCGβ positivity [13/54 (24.1%)]. However, it was significantly correlated with several clinicopathological features and unfavorable outcome (P < 0.05). hCGβ-overexpressing cell lines had increased invasiveness, migratory ability, and metastatic potential in mice (P < 0.01). Western blot, PCR, and microarray analyses showed hCGβ altered expression of EMT-related genes, including E-cadherin, phosphorylated SMAD2, SNAIL, and TWIST. hCGβ-induced SNAIL and TWIST overexpression levels were reversible by type I and type II TGF-β receptor inhibitors (P < 0.05). hCGβ thus induces EMT via the TGF-β signaling pathway, and it may represent a molecular target in CRC treatment.
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11
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Xu H, Haroon Al Rasheed MR, Wiley EL, Jin M. False-Positive Pregnancy Result in a Patient with Bone Mass. J Appl Lab Med 2017; 2:273-277. [PMID: 32630967 DOI: 10.1373/jalm.2017.022988] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2017] [Accepted: 04/03/2017] [Indexed: 11/06/2022]
Affiliation(s)
- Haoliang Xu
- Department of Pathology, University of Illinois at Chicago, Chicago, IL
| | | | - Elizabeth L Wiley
- Department of Pathology, University of Illinois at Chicago, Chicago, IL
| | - Ming Jin
- Department of Pathology, University of Illinois at Chicago, Chicago, IL
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12
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Li H, Wang X, Fang Y, Huo Z, Lu X, Zhan X, Deng X, Peng C, Shen B. Integrated expression profiles analysis reveals novel predictive biomarker in pancreatic ductal adenocarcinoma. Oncotarget 2017; 8:52571-52583. [PMID: 28881752 PMCID: PMC5581051 DOI: 10.18632/oncotarget.16732] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2016] [Accepted: 01/24/2017] [Indexed: 12/23/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the most lethal human malignant tumor, with a dismal 5-year survival rate of less than 5%. The lack of specific symptoms at early tumor stages and the paucity of biomarkers contribute to the poor diagnosis of pancreatic ductal adenocarcinoma. To improve prognosis, a screening biomarker for early diagnosis of pancreatic cancer is in urgent need. We searched the databases of expression profiling by array on GEO, aiming at comparing gene expression profile of matched pairs of pancreatic tumor and adjacent non-tumor tissues, and we screen out 4 suitable series of gene expression microarray data (“GSE15471”, “GSE18670”, “GSE28735” and “GSE58561”). After carefully analyzing, 13 DEGs (MYOF, SLC6A6, S100P, HK2, IFI44L, OSBPL3, IGF2BP3, PDK4, IL1R2, ERO1A, EGLN3, PLAC8 and ACSL5) are significantly differentially expressed in four microarray databases in common. After analyzing mRNA expression data and clinical follow-up survey provided in the TCGA database and clinicopathological data of 137 pancreatic ductal adenocarcinoma patients, we carefully demonstrated that three of these differentially expressed genes (ERO1A, OSBPL3 and IFI44L) are correlated with poor prognosis of pancreatic ductal adenocarcinoma patients. In addition, we revealed that cell–matrix adhesion and extracellular matrix were top significantly regulated pathways in pancreatic ductal adenocarcinoma and depicted two protein-protein interactions networks of extracellular matrix related Genes which are dysregulated according to 4 gene expression microarray data mentioned above (“GSE15471”, “GSE18670”, “GSE28735” and “GSE58561”), hoping to shed light on the etiology of PDAC and mechanisms of drug resistance in PDAC in this study.
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Affiliation(s)
- Hongzhe Li
- Department of Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China.,Research Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China.,Pancreatic Disease Centre, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, P.R. China
| | - Xinjing Wang
- Department of Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China.,Research Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China.,Pancreatic Disease Centre, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, P.R. China
| | - Yuan Fang
- Department of Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China.,Research Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China.,Pancreatic Disease Centre, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, P.R. China
| | - Zhen Huo
- Department of Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China.,Research Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China
| | - Xiongxiong Lu
- Department of Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China.,Pancreatic Disease Centre, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, P.R. China
| | - Xi Zhan
- Department of Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China.,Pancreatic Disease Centre, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, P.R. China
| | - Xiaxin Deng
- Department of Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China.,Pancreatic Disease Centre, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, P.R. China
| | - Chenghong Peng
- Department of Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China.,Pancreatic Disease Centre, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, P.R. China
| | - Baiyong Shen
- Department of Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China.,Research Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China.,Pancreatic Disease Centre, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, P.R. China
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13
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Rychlíková J, Vecka M, Jáchymová M, Macášek J, Hrabák P, Zeman M, Vávrová L, Řoupal J, Krechler T, Ák A. Osteopontin as a discriminating marker for pancreatic cancer and chronic pancreatitis. Cancer Biomark 2017; 17:55-65. [PMID: 27314293 DOI: 10.3233/cbm-160617] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
INTRODUCTION We analyzed concentrations of osteopontin (OPN) in patients with pancreatic ductal adenocarcinoma (PDAC) in order to determine firstly whether it is useful to distinguish between PDAC patients and those with chronic non-hereditary pancreatitis (CP) and type 2 diabetes mellitus (T2DM), and secondly whether OPN concentrations depend on the PDAC stage. METHODS Groups consisting of 64 patients with PDAC, 71 with CP, 67 with T2DM and 48 healthy controls (CON) were enrolled in the study. Controls were compared with regard to levels of OPN, oxidative stress markers, conventional tumor markers and other biochemical parameters. RESULTS Levels of OPN were higher in patients with PDAC compared with CP patients (P< 0.001), T2DM (P< 0.001) and CON (P< 0.001). There were increased OPN levels in CP patients in comparison with T2DM (P< 0.001) and CON (P< 0.001). Patients with PDAC in stage IV had higher OPN levels than PDAC patients in stage III (P< 0.01). There was no difference in OPN levels of PDAC patients in stage III compared to patients in stage II. CONCLUSION Our pilot study demonstrates the usefulness of estimating OPN levels to differentiate between pancreatic cancer and chronic pancreatitis. Higher OPN levels over 102 ng/ml could be a potential diagnostic biomarker for pancreatic cancer.
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Affiliation(s)
- Jana Rychlíková
- 4th Department of Internal Medicine, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic
| | - Marek Vecka
- 4th Department of Internal Medicine, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic
| | - Marie Jáchymová
- Institute of Clinical Biochemistry and Laboratory Diagnostics, First Faculty of Medicine Charles University in Prague, Prague, Czech Republic
| | - Jaroslav Macášek
- 4th Department of Internal Medicine, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic
| | - Petr Hrabák
- 4th Department of Internal Medicine, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic
| | - Miroslav Zeman
- 4th Department of Internal Medicine, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic
| | - Lucie Vávrová
- 4th Department of Internal Medicine, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic
| | - Jan Řoupal
- 3rd Department of Internal Medicine, First Faculty of Medicine Charles University and General University Hospital, Prague, Czech Republic
| | - Tomáš Krechler
- 4th Department of Internal Medicine, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic
| | - Aleš Ák
- 4th Department of Internal Medicine, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic
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14
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Lower plasma levels of glucose-dependent insulinotropic peptide (GIP) and pancreatic polypeptide (PP) in patients with ductal adenocarcinoma of the pancreas and their relation to the presence of impaired glucoregulation and weight loss. Pancreatology 2016; 17:89-94. [PMID: 28027898 DOI: 10.1016/j.pan.2016.12.004] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2016] [Revised: 11/14/2016] [Accepted: 12/15/2016] [Indexed: 12/11/2022]
Abstract
BACKGROUND The changes in gastrointestinal hormones associated with pancreatic ductal adenocarcinoma (PDAC) in patients with impaired glucoregulation have yet to be evaluated. The aim of this study was to determine plasma concentrations of selected gastrointestinal hormones in PDAC patients with and without diabetes and to compare them with levels found in Type 2 diabetic patients without cancer. METHODS In this study we examined plasma concentrations of glucose-dependent insulinotropic peptide (GIP), glucagon-like peptide 1 (GLP-1), pancreatic polypeptide (PP), peptide YY (PYY) and neuropeptide Y (NPY), and cytokines leptin and adiponectin in 94 patients with histologically confirmed PDAC. Thirty-nine patients with Type 2 diabetes without PDAC and 29 healthy individuals with no evidence of acute or chronic diseases were examined as controls. RESULTS Significantly lower plasma concentrations of GIP were found in PDAC patients with new-onset diabetes/prediabetes (n = 76), or in those with normal glucose regulation (n = 18), compared to patients with Type 2 diabetes without PDAC and controls (15.5 (3.7-64.5) or 6.5 (1.7-24.5) vs. 39.8 (15.1-104.7) and 28.8 (7.4-112.2) ng/L, p < 0.001); the same relationship was observed for PP (38.9 (10.2-147.9) or 28.1 (7.9-100.0) vs 89.1 (38.0-208.9) and 75.8 (30.1-190.6) ng/L, p < 0.01), respectively. The lowest levels of GIP and PP concentrations were found in PDAC patients with new-onset diabetes/prediabetes and weight loss > 2 kg (p < 0.001). CONCLUSIONS We conclude that GIP and PP plasma concentrations are lower in pancreatic cancer irrespective of the degree of glucose intolerance as compared to Type 2 diabetic patients and healthy controls. In new onset diabetes especially if associated with weight loss, these changes may represent a new clue for the diagnosis of PDAC.
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15
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Behrendt MA, van Rhijn BWG. Genetics and biological markers in urachal cancer. Transl Androl Urol 2016; 5:655-661. [PMID: 27785422 PMCID: PMC5071183 DOI: 10.21037/tau.2016.04.01] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2015] [Accepted: 03/08/2016] [Indexed: 01/28/2023] Open
Abstract
Urachal cancer (UraC) is a rare tumor entity that usually develops at the basis of the remnant embryologic urachus. Consisting of mostly adenocarcinomas, most patients present with secondary symptoms due to an advanced stage with urinary bladder infiltration. One third of patients are already metastasized at presentation rendering them unsuitable for curative surgical treatment. In order to improve staging, treatment and follow-up, adequate knowledge about the genetic origin and potential markers is necessary. This paper reviews the English literature until December 2015. Pathologists argue for and against metaplasia or remnant enteric cells as origin for the adenomatous tissue found in UraC. Mutations in KRAS, BRAF, GNAS and Her2 have been associated with UraC. Immunohistochemical (IHC) markers like CEA, 34βE12, Claudin-18 and RegIV are indicative for mucous producing UraC. So far, IHC markers fail as prognosticators when matched to clinical data. Little is known about serum markers for UraC. CEA, CA19-9, CA125 and CA724 are mentioned as being elevated in UraC by some reports. Regarding the literature for biological markers in UraC, knowledge is mostly derived from case reports or cohort studies mentioning markers or predictors. More genetic research is needed to show whether UraC stems from progenitor cells of the cloaca or is due to metaplasia of transitional cells. Few IHC markers have shown indicative potential for UraC. A useful panel for differential diagnostics and clinicopathologic prognostication needs to be developed. Serum markers show very little potential for neither diagnosis nor follow-up in UraC. Further research on larger cohorts is necessary.
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Affiliation(s)
- Mark A. Behrendt
- Department of Surgical Oncology, Division of Urology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands
- Department of Surgery, Division of Urology, University Hospital of Basel, Basel, Switzerland
| | - Bas W. G. van Rhijn
- Department of Surgical Oncology, Division of Urology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands
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16
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Liu P, Zhu Y, Liu L. Elevated serum CA72-4 levels predict poor prognosis in pancreatic adenocarcinoma after intensity-modulated radiation therapy. Oncotarget 2016; 6:9592-9. [PMID: 25860937 PMCID: PMC4496241 DOI: 10.18632/oncotarget.3562] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2015] [Accepted: 02/10/2015] [Indexed: 12/20/2022] Open
Abstract
Carbohydrate antigen 72-4 (CA72-4) is a human tumor-associated glycoprotein, commonly used as a tumor marker for diagnosing and predicting outcome in gastric and ovarian cancers. However, the relationship between serum CA72-4 levels and prognosis of pancreatic adenocarcinoma has not been fully elucidated. A total of 113 consecutive locally advanced pancreatic adenocarcinoma patients who underwent intensity-modulated radiation therapy (IMRT) with or without chemotherapy were enrolled in this study. Serum CA72-4 levels were analyzed using immunoenzymometric assays. The association between serum CA72-4 levels and prognosis was evaluated. Serum CA72-4 levels was related with lymph node metastasis (P<0.001). The median overall survival time was 14.0 months for patients with serum CA72-4 normal levels and 10.0 months for the elevated levels (P<0.001). Multivariate analysis identified that Serum CA72-4 concentration was a significant prognostic factor (P<0.001). The hazard ratio (HR) of elevated serum CA72-4 levels compared with normal serum CA72-4 levels was 2.34 (95% confidence interval [CI]: 1.46-3.73), after adjusted for gender and age. Based on this finding, Serum CA72-4 is a potential marker to predict lymph node metastasis and prognosis in pancreatic adenocarcinoma.
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Affiliation(s)
- Peng Liu
- Department of Radiotherapy, Zhejiang Cancer Hospital, Hangzhou, Zhejiang, China
| | - Yuan Zhu
- Department of Radiotherapy, Zhejiang Cancer Hospital, Hangzhou, Zhejiang, China
| | - Luying Liu
- Department of Radiotherapy, Zhejiang Cancer Hospital, Hangzhou, Zhejiang, China
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17
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Ferreira JA, Peixoto A, Neves M, Gaiteiro C, Reis CA, Assaraf YG, Santos LL. Mechanisms of cisplatin resistance and targeting of cancer stem cells: Adding glycosylation to the equation. Drug Resist Updat 2016; 24:34-54. [DOI: 10.1016/j.drup.2015.11.003] [Citation(s) in RCA: 117] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2015] [Revised: 11/09/2015] [Accepted: 11/18/2015] [Indexed: 02/06/2023]
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CĂINAP CĂLIN, NAGY VIORICA, GHERMAN ALEXANDRA, CETEAN SANZIANA, LASZLO ISTVAN, CONSTANTIN ANNEMARIE, CĂINAP SIMONA. Classic tumor markers in gastric cancer. Current standards and limitations. CLUJUL MEDICAL (1957) 2015; 88:111-5. [PMID: 26528057 PMCID: PMC4576775 DOI: 10.15386/cjmed-409] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 02/01/2015] [Accepted: 03/13/2015] [Indexed: 12/23/2022]
Abstract
The progress made in the last few years made available a large amount of information that needs to be integrated and ordered by oncologists. Tumor markers are one of the pieces that physicians need to fit into the bigger puzzle. This article will detail the most frequent etiologies for the surges in the carcinoembryonic antigen (CEA), cancer-related antigen 72-4 (CA 72-4), cancer-related antigen 19-9 (CA 19-9) serum levels and their indications. Although tumor markers are an invaluable asset to medical practice, their role in screening, diagnosis and oncologic treatment remains poorly standardized. Ongoing or future clinical trials will shed light on pending problems.
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Affiliation(s)
- CĂLIN CĂINAP
- Department of Oncology, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
- Department of Oncology, I. Chiricută Oncologic Institute, Cluj-Napoca, Romania
| | - VIORICA NAGY
- Department of Oncology, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
- Department of Oncology, I. Chiricută Oncologic Institute, Cluj-Napoca, Romania
| | - ALEXANDRA GHERMAN
- Department of Oncology, I. Chiricută Oncologic Institute, Cluj-Napoca, Romania
| | - SANZIANA CETEAN
- Department of Oncology, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - ISTVAN LASZLO
- Department of Oncology, I. Chiricută Oncologic Institute, Cluj-Napoca, Romania
| | - ANNE-MARIE CONSTANTIN
- Department of Morphology, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - SIMONA CĂINAP
- Department of Pediatric, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
- 2nd Pediatric Clinic Department, Emergency Pediatric Clinical Hospital, Cluj-Napoca, Romania
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Reitz D, Gerger A, Seidel J, Kornprat P, Samonigg H, Stotz M, Szkandera J, Pichler M. Combination of tumour markers CEA and CA19-9 improves the prognostic prediction in patients with pancreatic cancer. J Clin Pathol 2015; 68:427-33. [PMID: 25759406 DOI: 10.1136/jclinpath-2014-202451] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2014] [Accepted: 02/04/2015] [Indexed: 12/16/2022]
Abstract
AIMS Tumour markers including carcinoembryonic antigen (CEA) or carbohydrate antigen 19-9 (CA19-9) are frequently determined at the time of diagnosis in patients with pancreatic cancer. Several studies indicate a prognostic relevance of these markers in pancreatic cancer, but space for improvement with regard to the predictive accuracy and ability is given. In this work, the main focus is on mathematical combinations of these two tumour markers in order to validate an improvement of prognostic test results in terms of sensitivity and specificity. METHODS This retrospective study includes 393 patients with pancreatic cancer, who were treated between the years 2005 and 2012 at the Division of Oncology, Medical University of Graz, Austria. The goal of this study was to explore whether an appropriate combination of two tumour markers leads to a statistically significant improvement of the prognostic prediction. RESULTS Receiver operating characteristic curves comparison analyses with the classification variable cancer-specific survival showed that the mathematical product of two tumour markers (TM(product)= (CEA×CA19-9); area under the curve (AUC)=0.727; 95% CI 0.680 to 0.770) is significantly better than CEA alone (AUC=0.644; 95% CI 0.594 to 0.691; p=0.003) but not significant compared with CA19-9 (AUC=0.710; 95% CI 0.662 to 0.754; p=0.1215). A linear combination of CEA and CA19-9 (TM(linear)=(85×CEA+CA19-9); AUC=0.748; 95% CI 0.702 to 0.790) is significantly better than CEA (p<0.0001) as well as CA19-9 alone (p=0.0304). CONCLUSIONS Mathematical combinations of pretherapeutic tumour markers CEA and CA19-9 are feasible and can significantly improve the prognostic prediction in patients with pancreatic cancer.
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Affiliation(s)
- Daniel Reitz
- Division of Clinical Oncology, Department of Medicine, Medical University of Graz, Graz, Austria
| | - Armin Gerger
- Division of Clinical Oncology, Department of Medicine, Medical University of Graz, Graz, Austria
| | - Julia Seidel
- Division of Clinical Oncology, Department of Medicine, Medical University of Graz, Graz, Austria
| | - Peter Kornprat
- Division of General Surgery, Medical University of Graz, Graz, Austria
| | - Hellmut Samonigg
- Division of Clinical Oncology, Department of Medicine, Medical University of Graz, Graz, Austria
| | - Michael Stotz
- Division of Clinical Oncology, Department of Medicine, Medical University of Graz, Graz, Austria
| | - Joanna Szkandera
- Division of Clinical Oncology, Department of Medicine, Medical University of Graz, Graz, Austria
| | - Martin Pichler
- Division of Clinical Oncology, Department of Medicine, Medical University of Graz, Graz, Austria
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20
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Zhang Q, Burdette JE, Wang JP. Integrative network analysis of TCGA data for ovarian cancer. BMC SYSTEMS BIOLOGY 2014; 8:1338. [PMID: 25551281 PMCID: PMC4331442 DOI: 10.1186/s12918-014-0136-9] [Citation(s) in RCA: 61] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/10/2014] [Accepted: 12/11/2014] [Indexed: 12/18/2022]
Abstract
Background Over the past years, tremendous efforts have been made to elucidate the molecular basis of the initiation and progression of ovarian cancer. However, most existing studies have been focused on individual genes or a single type of data, which may lack the power to detect the complex mechanisms of cancer formation by overlooking the interactions of different genetic and epigenetic factors. Results We propose an integrative framework to identify genetic and epigenetic features related to ovarian cancer and to quantify the causal relationships among these features using a probabilistic graphical model based on the Cancer Genome Atlas (TCGA) data. In the feature selection, we first defined a set of seed genes by including 48 candidate tumor suppressors or oncogenes and an additional 20 ovarian cancer related genes reported in the literature. The seed genes were then fed into a stepwise correlation-based selector to identify 271 additional features including 177 genes, 82 copy number variation sites, 11 methylation sites and 1 somatic mutation (at gene TP53). We built a Bayesian network model with a logit link function to quantify the causal relationships among these features and discovered a set of 13 hub genes including ARID1A, C19orf53, CSKN2A1 and COL5A2. The directed graph revealed many potential genetic pathways, some of which confirmed the existing results in the literature. Clustering analysis further suggested four gene clusters, three of which correspond to well-defined cellular processes including cell division, tumor invasion and mitochondrial system. In addition, two genes related to glycoprotein synthesis, PSG11 and GALNT10, were found highly predictive for the overall survival time of ovarian cancer patients. Conclusions The proposed framework is effective in identifying possible important genetic and epigenetic features that are related to complex cancer diseases. The constructed Bayesian network has identified some new genetic/epigenetic pathways, which may shed new light into the molecular mechanisms of ovarian cancer. Electronic supplementary material The online version of this article (doi:10.1186/s12918-014-0136-9) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Qingyang Zhang
- Department of Statistics, Northwestern University, Evanston, IL60208, USA.
| | - Joanna E Burdette
- Department of Medicinal Chemistry and Pharmacognosy, University of Illinois, Chicago, 60607, IL, USA.
| | - Ji-Ping Wang
- Department of Statistics, Northwestern University, Evanston, IL60208, USA.
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Loc WS, Smith JP, Matters G, Kester M, Adair JH. Novel strategies for managing pancreatic cancer. World J Gastroenterol 2014; 20:14717-14725. [PMID: 25356034 PMCID: PMC4209537 DOI: 10.3748/wjg.v20.i40.14717] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2014] [Revised: 03/14/2014] [Accepted: 05/14/2014] [Indexed: 02/07/2023] Open
Abstract
With the incidence reports of pancreatic cancer increasing every year, research over the last several decades has been focused on the means to achieve early diagnosis in patients that are at a high risk of developing the malignancy. This review covers current strategies for managing pancreatic cancer and further discusses efforts in understanding the role of early onset symptoms leading to tumor progression. Recent investigations in this discussion include type 3c diabetes, selected biomarkers and pathways related to pancreatic intraepithelial neoplasia lesions, drug resistance, and advances in nanomedicine which may provide significant solutions for improving early detection and treatments in future medicine.
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22
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Tsai MM, Wang CS, Tsai CY, Chi HC, Tseng YH, Lin KH. Potential prognostic, diagnostic and therapeutic markers for human gastric cancer. World J Gastroenterol 2014; 20:13791-13803. [PMID: 25320517 PMCID: PMC4194563 DOI: 10.3748/wjg.v20.i38.13791] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2014] [Revised: 04/18/2014] [Accepted: 05/26/2014] [Indexed: 02/06/2023] Open
Abstract
The high incidence of gastric cancer (GC) and its consequent mortality rate severely threaten human health. GC is frequently not diagnosed until a relatively advanced stage. Surgery is the only potentially curative treatment. Thus, early screening and diagnosis are critical for improving prognoses in patients with GC. Gastroscopy with biopsy is an appropriate method capable of aiding the diagnosis of specific early GC tumor types; however, the stress caused by this method together with it being excessively expensive makes it difficult to use it as a routine method for screening for GC on a population basis. The currently used tumor marker assays for detecting GC are simple and rapid, but their use is limited by their low sensitivity and specificity. In recent years, several markers have been identified and tested for their clinical relevance in the management of GC. Here, we review the serum-based tumor markers for GC and their clinical significance, focusing on discoveries from microarray/proteomics research. We also review tissue-based GC tumor markers and their clinical application, focusing on discoveries from immunohistochemical research. This review provides a brief description of various tumor markers for the purposes of diagnosis, prognosis and therapeutics, and we include markers already in clinical practice and various forthcoming biomarkers.
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23
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Bilici A. Prognostic factors related with survival in patients with pancreatic adenocarcinoma. World J Gastroenterol 2014; 20:10802-10812. [PMID: 25152583 PMCID: PMC4138460 DOI: 10.3748/wjg.v20.i31.10802] [Citation(s) in RCA: 99] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2013] [Revised: 01/27/2014] [Accepted: 04/09/2014] [Indexed: 02/06/2023] Open
Abstract
The prognosis in patients with pancreatic cancer is poor and this cancer is the fourth leading cause of cancer-related death worldwide. Although surgical resection is the only curative treatment of choice for pancreatic cancer, the majority of patients are diagnosed at an advanced stage, thus only 10%-15% of them are suitable for curative resection and the overall survival is less than 5%. Chemotherapy for metastatic disease is to palliate symptoms of patients and to improve survival. Therefore, prognostic factors are important and a correct definition of poor prognostic factors may help to guide more aggressive adjuvant or aggressive treatment protocols in patients with pancreatic cancer. This article reviews the prognostic factors affecting survival of patients with pancreatic cancer in the light of recent advances in the literature.
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Nolen BM, Brand RE, Prosser D, Velikokhatnaya L, Allen PJ, Zeh HJ, Grizzle WE, Lomakin A, Lokshin AE. Prediagnostic serum biomarkers as early detection tools for pancreatic cancer in a large prospective cohort study. PLoS One 2014; 9:e94928. [PMID: 24747429 PMCID: PMC3991628 DOI: 10.1371/journal.pone.0094928] [Citation(s) in RCA: 70] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2013] [Accepted: 03/21/2014] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND The clinical management of pancreatic cancer is severely hampered by the absence of effective screening tools. METHODS Sixty-seven biomarkers were evaluated in prediagnostic sera obtained from cases of pancreatic cancer enrolled in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO). RESULTS The panel of CA 19-9, OPN, and OPG, identified in a prior retrospective study, was not effective. CA 19-9, CEA, NSE, bHCG, CEACAM1 and PRL were significantly altered in sera obtained from cases greater than 1 year prior to diagnosis. Levels of CA 19-9, CA 125, CEA, PRL, and IL-8 were negatively associated with time to diagnosis. A training/validation study using alternate halves of the PLCO set failed to identify a biomarker panel with significantly improved performance over CA 19-9 alone. When the entire PLCO set was used for training at a specificity (SP) of 95%, a panel of CA 19-9, CEA, and Cyfra 21-1 provided significantly elevated sensitivity (SN) levels of 32.4% and 29.7% in samples collected <1 and >1 year prior to diagnosis, respectively, compared to SN levels of 25.7% and 17.2% for CA 19-9 alone. CONCLUSIONS Most biomarkers identified in previously conducted case/control studies are ineffective in prediagnostic samples, however several biomarkers were identified as significantly altered up to 35 months prior to diagnosis. Two newly derived biomarker combinations offered advantage over CA 19-9 alone in terms of SN, particularly in samples collected >1 year prior to diagnosis. However, the efficacy of biomarker-based tools remains limited at present. Several biomarkers demonstrated significant velocity related to time to diagnosis, an observation which may offer considerable potential for enhancements in early detection.
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Affiliation(s)
- Brian M. Nolen
- University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania, United States of America
| | - Randall E. Brand
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh and University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, United States of America
| | - Denise Prosser
- University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania, United States of America
| | - Liudmila Velikokhatnaya
- University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania, United States of America
| | - Peter J. Allen
- Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America
| | - Herbert J. Zeh
- University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania, United States of America
- Department of Surgery, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
| | - William E. Grizzle
- Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
| | - Aleksey Lomakin
- Department of Physics, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America
| | - Anna E. Lokshin
- University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania, United States of America
- Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
- Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
- Department of Ob/Gyn, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
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Aberrant glycosylation as biomarker for cancer: focus on CD43. BIOMED RESEARCH INTERNATIONAL 2014; 2014:742831. [PMID: 24689054 PMCID: PMC3943294 DOI: 10.1155/2014/742831] [Citation(s) in RCA: 280] [Impact Index Per Article: 25.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/27/2013] [Accepted: 12/10/2013] [Indexed: 11/23/2022]
Abstract
Glycosylation is a posttranslational modification of proteins playing a major role in cell signalling, immune recognition, and cell-cell interaction because of their glycan branches conferring structure variability and binding specificity to lectin ligands. Aberrant expression of glycan structures as well as occurrence of truncated structures, precursors, or novel structures of glycan may affect ligand-receptor interactions and thus interfere with regulation of cell adhesion, migration, and proliferation. Indeed, aberrant glycosylation represents a hallmark of cancer, reflecting cancer-specific changes in glycan biosynthesis pathways such as the altered expression of glycosyltransferases and glycosidases. Most studies have been carried out to identify changes in serum glycan structures. In most cancers, fucosylation and sialylation are significantly modified. Thus, aberrations in glycan structures can be used as targets to improve existing serum cancer biomarkers. The ability to distinguish differences in the glycosylation of proteins between cancer and control patients emphasizes glycobiology as a promising field for potential biomarker identification. In this review, we discuss the aberrant protein glycosylation associated with human cancer and the identification of protein glycoforms as cancer biomarkers. In particular, we will focus on the aberrant CD43 glycosylation as cancer biomarker and the potential to exploit the UN1 monoclonal antibody (UN1 mAb) to identify aberrant CD43 glycoforms.
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26
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Karatolios K, Pankuweit S, Maisch B. Diagnostic value of biochemical biomarkers in malignant and non-malignant pericardial effusion. Heart Fail Rev 2013; 18:337-44. [PMID: 22638889 DOI: 10.1007/s10741-012-9327-x] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
The aim of this study was to examine the biochemical composition of pericardial effusions of different etiology and to evaluate the diagnostic utility of biochemical parameters and tumor markers to discriminate malignant from benign effusion. Pericardial and serum levels of biochemical parameters and tumor markers were compared in 105 patients who underwent pericardiocentesis and pericardioscopy with targeted epicardial biopsy. Etiologic diagnosis was based on pericardial fluid and epicardial biopsy analysis by cytology, histology, immunohistochemistry, microbiology and polymerase chain reaction. The total of 105 patients comprised 29 patients with malignant and 76 patients with non-malignant pericardial effusions (40 autoreactive, 28 viral, 5 postcardiotomy syndromes and 3 associated with systemic diseases). Malignant pericardial effusions had significantly higher pericardial fluid levels of the tumor markers CEA, CA 19-9, CA 72-4, SCC and NSE (p < 0.001, p = 0.002, p < 0.001, p = 0.004 and p < 0.001, respectively) as well as higher pericardial fluid hemoglobin (p < 0.001), pericardial fluid white blood cells (p = 0.003), pericardial fluid LDH (p < 0.001) and ratio of pericardial to serum LDH levels compared to benign effusions. None of the biochemical or cell-count parameters tested proved to be accurate enough for distinguishing malignant from benign effusions. However, measurement of pericardial CA 72-4 levels offered a high diagnostic accuracy for malignancy, particularly in bloody pericardial effusions. None of the biochemical parameters tested was useful for the discrimination of malignant from benign effusions. However, measurement of pericardial CA 72-4 levels in bloody pericardial effusions yielded a high diagnostic accuracy and thus offers the potential as a diagnostic tool to distinguish between malignant and benign effusions.
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Affiliation(s)
- Konstantinos Karatolios
- Department of Internal Medicine-Cardiology, Philipps-University Marburg, Baldingerstrasse, 35033, Marburg, Germany.
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27
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Poruk KE, Gay DZ, Brown K, Mulvihill JD, Boucher KM, Scaife CL, Firpo MA, Mulvihill SJ. The clinical utility of CA 19-9 in pancreatic adenocarcinoma: diagnostic and prognostic updates. Curr Mol Med 2013; 13:340-51. [PMID: 23331006 PMCID: PMC4419808 DOI: 10.2174/1566524011313030003] [Citation(s) in RCA: 173] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2012] [Revised: 10/12/2012] [Accepted: 10/15/2012] [Indexed: 12/29/2022]
Abstract
CA 19-9 and CEA are the most commonly used biomarkers for diagnosis and management of patients with pancreatic cancer. Since the original compendium by Steinberg in 1990, numerous studies have reported the use of CA 19-9 and, to a lesser extent, CEA in the diagnosis of pancreatic cancer. Here we update an evaluation of the accuracy of CA 19-9 and CEA, and, unlike previous reviews, focus on discrimination between malignant and benign disease instead of normal controls. In 57 studies involving 3,285 pancreatic carcinoma cases, the combined sensitivity of CA 19-9 was 78.2% and in 37 studies involving 1,882 cases with benign pancreatic disease the specificity of CA 19-9 was 82.8%. From the combined analysis of studies reporting CEA, the sensitivity was 44.2% (1,324 cases) and the specificity was 84.8% (656 cases). These measurements more appropriately reflect the expected biomarker accuracy in the differential diagnosis of patients with periampullary diseases. We also present a summary of the use of CA 19-9 as a prognostic tool and evaluate CA 19-9 diagnostic and prognostic utility in a 10-year, single institution experience.
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Affiliation(s)
- Katherine E. Poruk
- Department of Surgery and Oncological, University of Utah, Salt Lake City, UT 84132
| | - David Z. Gay
- Department of Surgery and Oncological, University of Utah, Salt Lake City, UT 84132
| | - Kurt Brown
- Department of Surgery and Oncological, University of Utah, Salt Lake City, UT 84132
| | - Jeffrey D. Mulvihill
- Department of Surgery and Oncological, University of Utah, Salt Lake City, UT 84132
| | - Kenneth M. Boucher
- Department of Sciences, University of Utah School of Medicine, and the Huntsman Cancer, University of Utah, Salt Lake City, UT 84132
- Department of Institute, University of Utah, Salt Lake City, UT 84132
| | - Courtney L. Scaife
- Department of Surgery and Oncological, University of Utah, Salt Lake City, UT 84132
- Department of Institute, University of Utah, Salt Lake City, UT 84132
| | - Matthew A. Firpo
- Department of Surgery and Oncological, University of Utah, Salt Lake City, UT 84132
- Department of Institute, University of Utah, Salt Lake City, UT 84132
| | - Sean J. Mulvihill
- Department of Surgery and Oncological, University of Utah, Salt Lake City, UT 84132
- Department of Institute, University of Utah, Salt Lake City, UT 84132
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Abstract
Accumulating data indicate that clinically available abdominal imaging tests such as EUS and MRI/MRCP can detect asymptomatic precursor benign (IPMN, PanIN) and invasive malignant pancreatic neoplasms, such as ductal adenocarcinoma, in individuals with an inherited predisposition. These asymptomatic FPCs detected have been more likely to be resectable, compared to symptomatic tumors. The most challenging part of screening high-risk individuals is the selection of individuals with high-grade precursor neoplasms for preventive treatment (ie, surgical resection before development of invasive cancer). Ongoing and future research should focus on formulating and validating a model for FPC risk and neoplastic progression using patient characteristics, imaging, and biomarkers. The comparative cost and effectiveness of various approaches for screening and surveillance of high-risk individuals also deserves study. For now, screening is best performed in high-risk individuals within the research protocols in academic centers with multidisciplinary teams with expertise in genetics, gastroenterology, radiology, surgery, and pathology.
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29
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Smith JP, Harms JF, Matters GL, McGovern CO, Ruggiero FM, Liao J, Fino KK, Ortega EE, Gilius EL, Phillips JA. A single nucleotide polymorphism of the cholecystokinin-B receptor predicts risk for pancreatic cancer. Cancer Biol Ther 2012; 13:164-74. [PMID: 22277584 DOI: 10.4161/cbt.13.3.18698] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
There currently are no tests available for early diagnosis or for the identification of patients at risk for development of pancreatic cancer. We report the discovery of single nucleotide polymorphism (SNP) in the cholecystokinin B receptor (CCKBR) gene predicts survival and risk of pancreatic cancer. Growth of human pancreatic cancer is stimulated by gastrin through the CCKBR and an alternatively spliced isoform of the CCKBR gene called CCKCR. One hundred and ten surgically resected benign and malignant pancreatic tissues as well as normal pancreas were prospectively evaluated for CCKBR genotype and protein expression. Analysis demonstrated the expression of the spliced isoform, CCKCR, was associated with a (SNP) (C > A) at position 32 of the intron 4 (IVS 4) of the CCKBR gene. Since the SNP is within an intron, it has not previously been identified in the GWAS studies. Only patients with the A/A or A/C genotypes, exhibited immunoreactivity to a selective CCKCR antibody. Survival among pancreatic cancer patients with the A-SNP was significantly shorter (p = 0.0001, hazard ratio = 3.63) compared with individuals with C/C genotype. Other variables such as surgical margins, lymph node status, histologic grade or adjuvant chemotherapy were not associated with survival. Furthermore, having one or two of the A-alleles was found to increase the risk of pancreatic adenocarcinoma by 174% (p = 0.0192) compared with the C/C wild type. Cancer cells transfected to overexpress the CCKCR demonstrated increased proliferation over controls. Genetic screening for this SNP may aid in early detection of pancreatic cancer in high risk subjects.
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Affiliation(s)
- Jill P Smith
- Penn State Hershey Medical Center, Medicine, Gastroenterology, Hershey, PA USA
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30
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Zhang DEX, Dai YDI, Yuan SX, Tao L. Prognostic factors in patients with pancreatic cancer. Exp Ther Med 2011; 3:423-432. [PMID: 22969906 DOI: 10.3892/etm.2011.412] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2011] [Accepted: 11/18/2011] [Indexed: 12/30/2022] Open
Abstract
The identification of prognostic factors for pancreatic cancer patients could provide insightful information for their management in the clinic. A total of 302 pancreatic cancer patients were enrolled in this study. The clinicopathological characteristics, treatment selection and laboratory test data were retrospectively retrieved from the medical records and follow-up data were obtained via telephone interview. Cox survival analysis was used to assess the potential prognostic factors, and survival curves were obtained by Kaplan-Meier analyses. The mortality rate of the patients was 83.4% (252/302) and the median survival of these patients was 6.1 months, with 1-, 2- and 3-year survival rates of 30.1 (91/302), 10.6 (32/302) and 2.6% (8/302), respectively. The most influential factors for the survival of these patients were the site of primary cancer, tumor stage, treatment selection, serum levels of glutamic-pyruvic transaminase, albumin, lactate dehydrogenase and hemoglobin, and white blood cell counts (P<0.05). The median survival of patients who did not receive any treatment or just received supportive treatment was 1.3 months, while the median overall survival of patients who underwent surgery, chemotherapy, biliary drainage therapy, arterial interventional chemotherapy and comprehensive treatment was 11.0, 7.3, 3.5, 9.0 and 11.0 months, respectively (P<0.05). Furthermore, single-drug chemotherapy was not statistically associated with patient survival in those who received the multi-drug regimen (P>0.05). However, the mortality risk of patients who received platinum chemotherapy was decreased [hazard ratio (HR)=0.56, 95% CI 0.35-0.88, P=0.011] compared to the patients who did not receive this treatment (P<0.05). Tumor stage, treatment selection, serum albumin levels, urea nitrogen, CA19-9, white blood cell and platelet counts were independent prognostic factors for the prediction of survival in pancreatic cancer. Future studies are required in order to verify these data. Chemotherapy with platinum regimens could improve overall survival in patients with pancreatic cancer.
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Affiliation(s)
- DE-Xiang Zhang
- Department of General Surgery, Jinshan Hospital Affiliated to Fudan University, Shanghai 200540
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31
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Morse MA, Bradley DA, Keler T, Laliberte RJ, Green JA, Davis TA, Inman BA. CDX-1307: a novel vaccine under study as treatment for muscle-invasive bladder cancer. Expert Rev Vaccines 2011; 10:733-42. [PMID: 21692696 DOI: 10.1586/erv.11.20] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Cancer vaccines have demonstrated clinical benefit, however greater efficacy could be achieved by enhancing their immunogenicity. Owing to cancer vaccines depending on uptake and cross-presentation of tumor antigens by antigen-presenting cells (APCs), we hypothesized that greater immunogenicity would accompany strategies that direct antigen to APC-expressed mannose receptors, initiating a pathway increasing class I and II presentation to T cells. CDX-1307 consists of a human monoclonal antibody targeting the mannose receptor, fused to the human chorionic gonadotropin-β chain (hCG-β), a tumor antigen frequently expressed by epithelial cancers including bladder cancer. In Phase I studies of cancer patients, CDX-1307 was well tolerated and induced significant hCG-β-specific cellular and humoral immune responses when co-administered with GM-CSF and the Toll-like receptor agonists resiquimod and poly-ICLC. An ongoing Phase II trial evaluates CDX-1307 in patients with newly diagnosed, resectable, hCG-β-expressing bladder cancer, where low tumor burden and early intervention may provide greater potential for benefit.
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Affiliation(s)
- Michael A Morse
- Duke University Medical Center, 10 Bryan Searle Drive, 477 Seeley G. Mudd Building, Durham, NC 27710, USA.
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Sharma C, Eltawil KM, Renfrew PD, Walsh MJ, Molinari M. Advances in diagnosis, treatment and palliation of pancreatic carcinoma: 1990-2010. World J Gastroenterol 2011; 17:867-97. [PMID: 21412497 PMCID: PMC3051138 DOI: 10.3748/wjg.v17.i7.867] [Citation(s) in RCA: 156] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2010] [Revised: 12/08/2010] [Accepted: 12/15/2010] [Indexed: 02/06/2023] Open
Abstract
Several advances in genetics, diagnosis and palliation of pancreatic cancer (PC) have occurred in the last decades. A multidisciplinary approach to this disease is therefore recommended. PC is relatively common as it is the fourth leading cause of cancer related mortality. Most patients present with obstructive jaundice, epigastric or back pain, weight loss and anorexia. Despite improvements in diagnostic modalities, the majority of cases are still detected in advanced stages. The only curative treatment for PC remains surgical resection. No more than 20% of patients are candidates for surgery at the time of diagnosis and survival remains quite poor as adjuvant therapies are not very effective. A small percentage of patients with borderline non-resectable PC might benefit from neo-adjuvant chemoradiation therapy enabling them to undergo resection; however, randomized controlled studies are needed to prove the benefits of this strategy. Patients with unresectable PC benefit from palliative interventions such as biliary decompression and celiac plexus block. Further clinical trials to evaluate new chemo and radiation protocols as well as identification of genetic markers for PC are needed to improve the overall survival of patients affected by PC, as the current overall 5-year survival rate of patients affected by PC is still less than 5%. The aim of this article is to review the most recent high quality literature on this topic.
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33
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Diagnostic management of pancreatic cancer. Cancers (Basel) 2011; 3:494-509. [PMID: 24212626 PMCID: PMC3756374 DOI: 10.3390/cancers3010494] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2010] [Revised: 01/20/2011] [Accepted: 01/24/2011] [Indexed: 12/12/2022] Open
Abstract
Pancreatic cancer is one of the most deadly solid tumors, with an overall 5-year survival rate of less than 5%. Due to a non-specific clinical presentation, it is often diagnosed at an advanced stage and is rarely amenable for curative treatment. Therefore early diagnosis and appropriate staging are still essential to define the best care and to improve patient survival. Several imaging modalities are currently available for the evaluation of pancreatic cancer. This review focuses on different techniques and discusses the diagnostic management of patients with pancreatic cancer. This review was conducted utilizing Pubmed and was limited to papers published within the last 5 years. The search key words pancreatic cancer, pancreatic adenocarcinoma, pancreatic tumors, diagnosis, radiology, imaging, nuclear imaging, endoscopy, endoscopic ultrasound and biochemical markers were used.
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Iles RK, Delves PJ, Butler SA. Does hCG or hCGβ play a role in cancer cell biology? Mol Cell Endocrinol 2010; 329:62-70. [PMID: 20654692 DOI: 10.1016/j.mce.2010.07.014] [Citation(s) in RCA: 57] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2010] [Revised: 06/22/2010] [Accepted: 07/13/2010] [Indexed: 01/31/2023]
Abstract
The role that hCG might play in the oncogenic process in cancer is certainly complex. We know that the expression of hCG and its beta subunit is a widespread phenomenon which has been described in many cancer subtypes. However, hCG's involvement in breast cancer has been antithetical: the detection of ectopically expressed hCG(β) by breast tumors has been employed as a biomarker of malignancy, and hCG has been proposed as a ligand vehicle for toxic drugs, with the aim of targeting the LH/hCG receptor which is reported to be expressed by malignant breast tissue. However, it has also been proposed that hCG is a protective agent against the development of breast cancer, leading some to advocate hCG administration to non-pregnant women as a prophylactic measure against cancer. Nevertheless, suggestions that hCG is involved in the angiogenesis, metastasis and immune escape that are central to cancer progression - are phenomena which clearly apply to breast cancer. Indeed, a tumor vaccine based upon hCG has very recently been shown to protect against mammary tumors in mice. We propose that this apparent paradox is resolved if the free beta subunit of hCG produced by tumors acts as an autocrine anti-apoptotic and angiogenic growth factor, whilst intact heterodimeric hCG, as in pregnancy, is part of developmental signaling that initiates tissue differentiation (including breast ductal tissue development), and hence reduces the population of stem-like cells which are susceptible to oncogenic factors.
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Affiliation(s)
- R K Iles
- Centre for Investigative and Diagnostic Oncology, Middlesex University, The Burroughs, Hendon, London NW4 4BT, UK.
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35
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Reis CA, Osorio H, Silva L, Gomes C, David L. Alterations in glycosylation as biomarkers for cancer detection. J Clin Pathol 2010; 63:322-9. [PMID: 20354203 DOI: 10.1136/jcp.2009.071035] [Citation(s) in RCA: 320] [Impact Index Per Article: 21.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
Glycoconjugates constitute a major class of biomolecules which include glycoproteins, glycosphingolipids and proteoglycans. Glycans are involved in several physiological and pathological conditions, such as host-pathogen interactions, cell differentiation, migration, tumour invasion and metastisation, cell trafficking and signalling. Cancer is associated with glycosylation alterations in glycoproteins and glycolipids. This review describes various aspects of protein glycosylation with the focus on alterations associated with human cancer. The application of these glycosylation modifications as biomarkers for cancer detection in tumour tissues and serological assays is summarised.
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Affiliation(s)
- Celso A Reis
- Institute of Molecular Pathology and Immunology of the University of Porto - IPATIMUP, Porto 4200-465, Portugal.
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Cole LA, Khanlian SA, Muller CY. Normal Production of Human Chorionic Gonadotropin in Perimenopausal and Menopausal Women and After Oophorectomy. Int J Gynecol Cancer 2009; 19:1556-9. [DOI: 10.1111/igc.0b013e3181a40cf2] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023] Open
Abstract
Background:The normal pituitary production of human chorionic gonadotropin (hCG) alongside luteinizing hormone, and its presence in women after bilateral oophorectomy, during perimenopause and menopause, as measured in serum and urine, has been known for 30 years and is described in numerous publications. Last year our group discussed this finding in a correspondence to the editor in the March 15th issue of New England Journal of Medicine, yet the misinterpretation of low-level hCG in these women seems to have increased in magnitude.Methods:This is an outcomes study of 36 cases of menopausal hCG referred to the USA hCG Reference Service over a 1-year period, from March 2007 to March 2008.Results:Eight cases occurred in women after oophorectomy, 28 were women in menopause/perimenopause. Surgery was postponed in 5 (14%) of 36 cases, and in 3 cases (8%), chemotherapy was unnecessarily administered. In 2 cases, computed tomography scans were cancelled. The average hCG detected was 10 ± 7.2 IU/L in cases receiving an oophorectomy and 9.8 ± 6.7 in perimenopause and 11 ± 6.2 IU/L in menopause cases.Conclusions:Low-level hCG production in woman in physiologic perimenopause, in menopause, or in women with prior bilateral oophorectomy is a normal biologic and biochemical phenomenon. Management protocols in all fields need to be changed to accept pituitary hCG as normal and recognize the clinical maneuvers that will secure the diagnosis. Understanding this physiology will avoid needless delays in necessary therapies such as organ transplant procedures and will limit the misadventure of prescribing unnecessary cancer treatments.
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Detection and quantification of D-glucuronic acid in human bile using 1H NMR spectroscopy: relevance to the diagnosis of pancreatic cancer. MAGNETIC RESONANCE MATERIALS IN PHYSICS BIOLOGY AND MEDICINE 2009; 22:267-75. [PMID: 19390887 DOI: 10.1007/s10334-009-0171-5] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Received: 12/23/2008] [Revised: 04/03/2009] [Accepted: 04/06/2009] [Indexed: 01/18/2023]
Abstract
OBJECTIVE There are no specific biomarkers available for the definitive diagnosis of pancreatic cancer. Analysis of D-glucuronic acid (GlcUA) in bile could be valuable in this regard. MATERIALS AND METHODS Bile samples obtained from patients with pancreatic cancer (n = 4), chronic pancreatitis (n = 3) and control patients with biliary obstruction (n = 10) were analyzed by (1)H NMR spectroscopy. GlcUA was quantified from the peak area of the alpha-(1)CH signal (at 5.24 ppm) obtained by deconvolution. RESULTS GlcUA was detected in human bile by one-dimensional (1)H NMR and two-dimensional (1)H-(1)H COSY and TOCSY experiments. Quantification of GlcUA was achieved by measuring the peak area of the alpha-(1)CH signal using CPMG experiment, and the quantities of GlcUA were calibrated to account for the attenuation due to T (2) relaxation. GlcUA was observed at elevated levels in bile samples obtained from pancreatic cancer patients, whereas it was either absent or found in negligible amounts in control and chronic pancreatitis patients. The reason for the presence of elevated levels of GlcUA could be the hydrolysis of biliary bilirubin diglucuronide by beta-glucuronidase, released excessively from pancreatic tissue during the course of malignancy. CONCLUSION Analysis of D-glucuronic acid in bile could be valuable in the detection of pancreatic cancer, and detecting GlcUA by in vivo (1)H MRS has the potential to help in the non-invasive diagnosis of pancreatic cancer. Given that only four cancer patients have been studied so far, the new biomarker is regarded as a preliminary finding, but one that warrants further investigation.
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Gao Y, Lu H, Yuan Z, Zhu R. Tumor Markers in Thyroid Carcinoma With Pulmonary Metastases After Thyroidectomy. Lab Med 2009. [DOI: 10.1309/lm8fzxw08brjsjsr] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023] Open
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Cole LA, Khanlian SA, Muller CY. Detection of perimenopause or postmenopause human chorionic gonadotropin: an unnecessary source of alarm. Am J Obstet Gynecol 2008; 198:275.e1-7. [PMID: 18313448 DOI: 10.1016/j.ajog.2007.09.034] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2007] [Revised: 06/25/2007] [Accepted: 09/19/2007] [Indexed: 02/08/2023]
Abstract
OBJECTIVE The normal pituitary production of human chorionic gonadotropin alongside luteinizing hormone, measurable in menopausal serum and urine was initially reported over 3 decades ago and has been described in numerous subsequent publications. Unfortunately, delays or cancellations of important medical procedures and use of needless chemotherapy still occurs because of the finding of human chorionic gonadotropin in perimenopausal and postmenopausal woman. We describe the problem and a concise approach to this management dilemma in menopausal women. STUDY DESIGN This is an outcomes study of 36 cases of perimenopausal and postmenopausal human chorionic gonadotropin evaluated in cases referred to the USA hCG Reference Service. RESULTS By report of the provided records, in 6 of 36 cases, unneeded chemotherapy was given for assumed recurrent gestational trophoblastic disease. In 9 cases, surgery was cancelled or postponed and in 3 cases renal transplantation was cancelled at the time of locating a matched donor kidney. In all cases the measured human chorionic gonadotropin was due to menopausal production of pituitary human chorionic gonadotropin. The average human chorionic gonadotropin detected in perimenopausal cases was 6.4 +/- 3.2 IU/L, and in postmenopausal cases was 11.6 +/- 7.0 IU/L or significantly higher. In 24 cases, therapeutic doses of high-estrogen birth control pill were used to confirm pituitary origin with 23 cases demonstrating successful human chorionic gonadotropin suppression. CONCLUSION Low levels of human chorionic gonadotropin production in the perimenopausal and postmenopausal state is a normal physiologic phenomenon. Provider education is warranted and management protocols are suggested in all health-related fields to clarify the normality of low level pituitary human chorionic gonadotropin production. Understanding this physiology will avoid delays in necessary therapies such as organ transplants, and will limit the misadventure of prescribing unnecessary treatments for presumed gestational malignancy.
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Kuhlmann KF, van Till JO, Boermeester MA, de Reuver PR, Tzvetanova ID, Offerhaus GJA, ten Kate FJ, Busch OR, van Gulik TM, Gouma DJ, Crawford HC. Evaluation of matrix metalloproteinase 7 in plasma and pancreatic juice as a biomarker for pancreatic cancer. Cancer Epidemiol Biomarkers Prev 2007; 16:886-91. [PMID: 17507610 PMCID: PMC4516164 DOI: 10.1158/1055-9965.epi-06-0779] [Citation(s) in RCA: 60] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Differentiating between periampullary carcinoma and chronic pancreatitis with an inflammatory mass is difficult. Consequently, 6% to 9% of pancreatic resections for suspected carcinoma are done inappropriately for chronic pancreatitis. Here, we test if matrix metalloproteinase 7 (MMP-7), a secreted protease frequently expressed in pancreatic carcinoma, can be measured in plasma, pancreatic, and duodenal juice, and if it can distinguish between periampullary carcinoma and chronic pancreatitis. Ninety-four patients who underwent pancreatic surgery for a (peri)pancreatic neoplasm (n = 63) or chronic pancreatitis (n = 31) were analyzed. Median plasma MMP-7 levels were significantly higher in carcinoma (1.95 ng/mL; interquartile range, 0.81-3.22 ng/mL) compared with chronic pancreatitis and benign disease (0.83 ng/mL; interquartile range, 0.25-1.21 ng/mL; P < 0.01). MMP-7 levels in pancreatic juice were higher, although not significantly, in carcinoma (62 ng/mg protein; interquartile range, 18-241 ng/mg protein) compared with chronic pancreatitis and benign disease (23 ng/mg protein; interquartile range, 8.5-99 ng/mg protein; P = 0.17). MMP-7 levels in duodenal juice were universally low. At an arbitrary cutoff of 1.5 ng/mL in plasma, positive and negative predictive values were 83% and 57%, respectively, values comparable to those of today's most common pancreatic tumor marker, carbohydrate antigen 19-9 (CA19-9; 83% and 53%, respectively). Positive and negative likelihood ratios for plasma MMP-7 were 3.35 and 0.52, respectively. The area under the receiver operating characteristic curve for MMP-7 was 0.73 (95% confidence interval, 0.63-0.84) and for CA19-9, 0.75 (95% confidence interval, 0.64-0.85). Combined MMP-7 and CA19-9 assessment gave a positive predictive value of 100%. Thus, plasma MMP-7 levels discriminated between patients with carcinoma and those with chronic pancreatitis or benign disease. The diagnostic accuracy of plasma MMP-7 alone is not sufficient to determine treatment strategy in patients with a periampullary mass, but combined evaluation of plasma MMP-7 with CA19-9 and other markers may be clinically useful.
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Affiliation(s)
- Koert F.D. Kuhlmann
- Department of Surgery, Academic Medical Center of the University of Amsterdam, Amsterdam, the Netherlands
| | - J.W. Olivier van Till
- Department of Surgery, Academic Medical Center of the University of Amsterdam, Amsterdam, the Netherlands
| | - Marja A. Boermeester
- Department of Surgery, Academic Medical Center of the University of Amsterdam, Amsterdam, the Netherlands
| | - Philip R. de Reuver
- Department of Surgery, Academic Medical Center of the University of Amsterdam, Amsterdam, the Netherlands
| | - Iva D. Tzvetanova
- Department of Pharmacological Sciences, Stony Brook University, Stony Brook, New York
| | - G. Johan A. Offerhaus
- Department of Pathology, Academic Medical Center of the University of Amsterdam, Amsterdam, the Netherlands
| | - Fiebo J.W. ten Kate
- Department of Pathology, Academic Medical Center of the University of Amsterdam, Amsterdam, the Netherlands
| | - Olivier R.C. Busch
- Department of Surgery, Academic Medical Center of the University of Amsterdam, Amsterdam, the Netherlands
| | - Thomas M. van Gulik
- Department of Surgery, Academic Medical Center of the University of Amsterdam, Amsterdam, the Netherlands
| | - Dirk J. Gouma
- Department of Surgery, Academic Medical Center of the University of Amsterdam, Amsterdam, the Netherlands
| | - Howard C. Crawford
- Department of Pharmacological Sciences, Stony Brook University, Stony Brook, New York
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Inhibition of tumor growth in vitro and in vivo by a monoclonal antibody against human chorionic gonadotropin beta. Immunol Lett 2007; 114:94-102. [PMID: 17964664 DOI: 10.1016/j.imlet.2007.09.005] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2007] [Accepted: 09/12/2007] [Indexed: 11/24/2022]
Abstract
Human chorionic gonadotropin (hCG) beta-subunit (hCGbeta) has been detected in a wide variety of tumors and implicated in tumor maintenance and progression. To better facilitate the investigation of the expression and biological roles of hCGbeta, we generated a set of monoclonal antibodies (mAbs) against hCGbeta by the approach of DNA immunization. All the generated mAbs worked well in detecting native hCGbeta antigen, while some of them were surprisingly found to exhibit potential cytotoxicity to tumor cells in our preliminary experiments. Here, one of those cytotoxic anti-hCGbeta mAb 6H1 was evaluated in detail for its anti-tumor efficacy in vitro and in vivo. 6H1 showed high binding specificity to hCGbeta, which was analyzed by Western blot and ELISA as well as indirect immunofluorescence assay. Treatment with 6H1 inhibited the growth of a panel of hCGbeta-expressing tumor cell lines (HeLa, HL-60, HepG2, SMMC-7721, PC-3) in vitro. Moreover, 6H1 significantly delayed the growth of HeLa-borne tumors in nude mice and prolonged the survival of tumor-bearing mice. The anti-tumor effect of 6H1 was associated with the induction of apoptosis, which was estimated by Hoechst 33258 staining, DNA ladder assay and flow cytometry. Collectively, 6H1 revealed potent anti-tumor activity in vitro and in vivo and therefore may be an effective therapeutic candidate for immuno-intervention of cancers that ectopically express hCGbeta.
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Iles RK. Ectopic hCGbeta expression by epithelial cancer: malignant behaviour, metastasis and inhibition of tumor cell apoptosis. Mol Cell Endocrinol 2007; 260-262:264-70. [PMID: 17069968 DOI: 10.1016/j.mce.2006.02.019] [Citation(s) in RCA: 83] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2005] [Accepted: 02/19/2006] [Indexed: 11/28/2022]
Abstract
Ectopic expression of the beta-subunit of human chorionic gonadotropin (hCG) is now a recognized phenomenon in 20-40% of all common epithelial carcinoma arising from mucosal epithelia such as bladder, cervix, lung and naso-pharynx. Recent studies have shown that it acts as an autocrine growth factor by inhibiting apoptosis. Structural homology and in vitro studies suggest that it may achieve this by inhibition of the transforming growth factor beta (TGFbeta) receptor complex. Such a molecular mechanism would go some way to explaining ectopic hCGbeta's association with poor prognosis and tumors that will rapidly progress to metastasis.
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Affiliation(s)
- R K Iles
- Department of Biomedical Sciences, Institute of Social and Health Research, Middlesex University, Queensway, Enfield Middlesex EN3 4SA, UK.
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Goonetilleke KS, Siriwardena AK. Systematic review of carbohydrate antigen (CA 19-9) as a biochemical marker in the diagnosis of pancreatic cancer. Eur J Surg Oncol 2006; 33:266-70. [PMID: 17097848 DOI: 10.1016/j.ejso.2006.10.004] [Citation(s) in RCA: 604] [Impact Index Per Article: 31.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2006] [Accepted: 10/03/2006] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Although many biochemical markers have been examined in pancreatic cancer none are definitive for pre-operative diagnosis. This systematic review examines studies using biochemical markers for the diagnosis of pancreatic cancer in order to appraise their role in contemporary management algorithms. METHODS A search of the MEDLINE database was undertaken using the key words pancreatic neoplasm and serum tumour marker. Only studies providing original data on sensitivity and specificity are included and data are presented on diagnostic accuracy, effect of cholestasis and the relation of tumour stage to blood levels of markers. RESULTS CA 19-9 is the most extensively evaluated with pooled data from 2283 patients. The median sensitivity of CA 19-9 for diagnosis is 79 (70-90%) and median specificity 82 (68-91%). CA 19-9 elevation in non-malignant jaundice results in a fall in specificity. Combination with other markers improves accuracy. CONCLUSION As the most extensively evaluated marker, CA 19-9 should be used in contemporary algorithms for the diagnosis of pancreatic cancer. Elevated values should be repeated after relief of jaundice.
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Affiliation(s)
- K S Goonetilleke
- Department of Surgery, Hepatobiliary Surgical Unit, Manchester Royal Infirmary, Oxford Road, Manchester M13 9WL, UK
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Simpson AJG, Caballero OL, Jungbluth A, Chen YT, Old LJ. Cancer/testis antigens, gametogenesis and cancer. Nat Rev Cancer 2005; 5:615-25. [PMID: 16034368 DOI: 10.1038/nrc1669] [Citation(s) in RCA: 1184] [Impact Index Per Article: 59.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Cancer/testis (CT) antigens, of which more than 40 have now been identified, are encoded by genes that are normally expressed only in the human germ line, but are also expressed in various tumour types, including melanoma, and carcinomas of the bladder, lung and liver. These immunogenic proteins are being vigorously pursued as targets for therapeutic cancer vaccines. CT antigens are also being evaluated for their role in oncogenesis--recapitulation of portions of the germline gene-expression programme might contribute characteristic features to the neoplastic phenotype, including immortality, invasiveness, immune evasion, hypomethylation and metastatic capacity.
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Affiliation(s)
- Andrew J G Simpson
- Ludwig Institute for Cancer Research, New York Branch at Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10021, USA.
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Kopper L, Zalatnai A, Tímár J. Genomics of pancreatic cancer: does it make any improvement in diagnosis, prognosis and therapy? Pathol Oncol Res 2005; 11:69-73. [PMID: 15999149 DOI: 10.1007/bf02893369] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2005] [Accepted: 06/11/2005] [Indexed: 12/14/2022]
Abstract
Pancreatic cancer (PanC) is an extremely lifethreatening neoplasm due to its late discovery, rapid progression and resistance to chemo- and radiotherapy. In the past years a significant research attention turned to this cancer. Extensive genomic analysis of PanC revealed numerous alterations, however, none of them emerged yet as a key regulator of tumor progression. Our increasing knowledge on the molecular targets in various cancer types started to change their management. Examples of success of the molecular therapies (in CML, GIST, NSCLC) may initiate more activity in pancreatic cancer as well.
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Affiliation(s)
- László Kopper
- 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, H-1085, Hungary.
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Abstract
Pancreatic cancer remains a devastating and difficult disease to diagnose and successfully treat. Its incidence increases with age, with 60% of patients being over the age of 65 at presentation. Due to the insidious nature and asymptomatic onset of pancreatic cancer approximately 85% of patients present with disseminated or locally advanced disease resulting in a very poor prognosis. In the past the elderly patient, who may be felt to be too frail for operative procedures or further therapy, may have missed out on optimal treatment. In this article we review the investigation and treatment of pancreatic cancer and examine current evidence with regard to pancreatic cancer in the elderly. The evidence suggests that surgical resection can be performed safely in patients who are fit for surgery in specialist centres but may require more intensive post-operative rehabilitation.
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Affiliation(s)
- Susannah Shore
- Division of Surgery and Oncology, University of Liverpool, 5th Floor UCD Building, Daulby Street, Liverpool, L69 3GA, United Kingdom
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