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Abdulrazaq JA, Zakari MA, Ibrahim Y, Ahmad H. Expression of cyclooxygenase-2 (COX-2) in colorectal carcinoma in an indigenous African population of Kano, Nigeria. Ecancermedicalscience 2024; 18:1816. [PMID: 40171463 PMCID: PMC11959126 DOI: 10.3332/ecancer.2024.1816] [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: 06/01/2024] [Indexed: 01/05/2025] Open
Abstract
Background cyclooxygenases-2 (COX-2) over-expression has been noticed in colorectal cancers (CRCs) with adverse outcomes, serving as a potential marker for prognosis, targeted therapy and as a window in CRC prevention. Unfortunately, there are scarce data regarding COX-2 expression in CRC in Africa where CRC incidence is on the increase with younger age affectation and unfavourable outcomes. Aims This retrospective study aims to determine the proportion of CRCs that over-express COX-2 and document any relationship between COX-2 over-expression with clinicopathological features such as histologic subtype, tumour grade, age and sex. Methods All the 139 CRCs that were histologically diagnosed at Aminu Kano Teaching Hospital over a 5-year period were included, but only 124 Formalin-fixed paraffin-embedded tissue blocks were sectioned and stained with COX-2 antibody. COX-2 expression was scored for distribution (no cells = 0, 1%-10% = 1, 11%-50% = 2, 51%-80% = 3, 81%-100% = 4) and intensity (no stain = 0; weak = 1; moderate = 2, strong = 3). The immunoreactive score (IRS) is a product of intensity (I) and distribution (D) as: 9-12 strongly +, 5-8 moderately +, 1-4 weakly + and 0 negative. Over-expression of COX-2 is an IRS of 5-12. Outcomes were statistically evaluated with clinicopathological data. Results The CRCs occurred more commonly in males (M: F, 2:1), in the middle age group (mostly between 30 and 59 years), and 51.1% of cases occurred before 50 years and peaked in the 6th decade. Over-expression of COX-2 was observed in 46.8% (58/124) and was strongly associated with adenocarcinoma (ADC) not otherwise specified (NOS) (moderately and poorly differentiated tumours) but not with age or sex. Conclusion The over-expression of COX-2 was significantly associated with ADC NOS (moderately and poorly differentiated tumours), indicating that it may influence the outcome of CRCs with possible variation in tumour subtype.
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Affiliation(s)
- Jimoh Ajanaku Abdulrazaq
- Department of Pathology, Federal University of Health Sciences Azare, Azare 751101, Bauchi, Nigeria
| | | | - Yusuf Ibrahim
- Department of Pathology, Aminu Kano Teaching Hospital, Kano 700101, Nigeria
| | - Hamza Ahmad
- Department of Pathology, Aminu Kano Teaching Hospital, Kano 700101, Nigeria
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2
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Bádon ES, Beke L, Mokánszki A, András C, Méhes G. Carbonic Anhydrase IX Expression and Treatment Response Measured in Rectal Adenocarcinoma Following Neoadjuvant Chemo-Radiotherapy. Int J Mol Sci 2023; 24:ijms24032581. [PMID: 36768903 PMCID: PMC9916425 DOI: 10.3390/ijms24032581] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Revised: 01/16/2023] [Accepted: 01/24/2023] [Indexed: 01/31/2023] Open
Abstract
The overexpression of the pH regulator carbonic anhydrase IX (CAIX) due to hypoxic/metabolic stress was reported in various tumors as an adverse prognostic feature. Our retrospective study aimed to investigate the general pattern and dynamics of CAIX expression in rectal adenocarcinoma following preoperative neoadjuvant therapy (NAT) in matched initial biopsy and surgical resection samples. A total of 40/55 (72.72%) of the post-treatment samples showed partial CAIX expression, frequently in the proximity of hypoxic tumor areas. CAIX expression showed a significant increase in post-treatment tumors (mean% 21.8 ± 24.9 SD vs. 39.4 ± 29.4 SD, p < 0.0001), that was not obvious in untreated tumors (mean% 15.0 ± 21.3 SD vs. 20 ± 23.02, p = 0.073). CAIXhigh phenotype was associated with mutant KRAS status and lack of pathological regression (WHO Tumor Regression Grade 4 and 5). However, the adverse effect of CAIX on overall or progression-free survival could not be statistically confirmed. In conclusion, the dynamic upregulation of CAIX expression is a general feature of rectal adenocarcinoma following neoadjuvant chemo-radiotherapy indicating therapy-induced metabolic reprogramming and cellular adaptation. A synergism of the CAIX-associated regulatory pathways and the mutant KRAS oncogenic signaling most likely contributes to therapy resistance and survival of residual cancer.
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Affiliation(s)
- Emese Sarolta Bádon
- Department of Pathology, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary
| | - Lívia Beke
- Department of Pathology, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary
| | - Attila Mokánszki
- Department of Pathology, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary
| | - Csilla András
- Department of Oncology, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary
| | - Gábor Méhes
- Department of Pathology, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary
- Correspondence: ; Tel.: +36-5-2411-600
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John A, Vetrivel U, Sivashanmugam M, Natarajan SK. Microsecond Simulation of the Proteoglycan-like Region of Carbonic Anhydrase IX and Design of Chemical Inhibitors Targeting pH Homeostasis in Cancer Cells. ACS OMEGA 2020; 5:4270-4281. [PMID: 32149257 PMCID: PMC7057697 DOI: 10.1021/acsomega.9b04203] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/09/2019] [Accepted: 01/08/2020] [Indexed: 05/09/2023]
Abstract
Carbonic anhydrase IX (CAIX) is a membrane-bound enzyme associated with tumor hypoxia and found to be over expressed in various tumor conditions. Targeting CAIX catalytic activity is proven to be efficient modality in modulating pH homeostasis in cancer cells. Proteoglycan-like (PG) region is unique to CAIX and is proposed to serve as an antenna enhancing the export of protons in conjunction with facilitated efflux of lactate ions via monocarboxylate transporters. Moreover, the PG region is also reported to contribute to the assembly and maturation of focal adhesion links during cellular attachment and dispersion on solid supports. Thus, drug targeting of this region shall efficiently modulate pH homeostasis and cell adhesion in cancer cells. As the PG region is intrinsically disordered, the complete crystal structure is not elucidated. Hence, in this study, we intend to sample the conformational landscape of the PG region at microsecond scale simulation in order to sample the most probable conformations that shall be utilized for structure-based drug design. In addition, the sampled conformations were subjected to high-throughput virtual screening against NCI and Maybridge datasets to identify potential hits based on consensus scoring and validation by molecular dynamics simulation. Further, the identified hits were experimentally validated for efficacy by in vitro and direct enzymatic assays. The results reveal 5-(2-aminoethyl)-1,2,3-benzenetriol to be the most promising hit as it showed significant CAIX inhibition at all levels of in silico and experimental validation.
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Affiliation(s)
- Arun John
- Centre
for Bioinformatics, Kamalnayan Bajaj Institute for Research in Vision
and Ophthalmology, Vision Research Foundation,
Sankara Nethralaya, Chennai 600 006, Tamil Nadu, India
- School
of Chemical and Biotechnology, SASTRA Deemed
University, Thanjavur, Tamil Nadu, India
| | - Umashankar Vetrivel
- Centre
for Bioinformatics, Kamalnayan Bajaj Institute for Research in Vision
and Ophthalmology, Vision Research Foundation,
Sankara Nethralaya, Chennai 600 006, Tamil Nadu, India
- E-mail: . Phone: +91-44-28271616. Fax: +91-44-28254180
| | - Muthukumaran Sivashanmugam
- Centre
for Bioinformatics, Kamalnayan Bajaj Institute for Research in Vision
and Ophthalmology, Vision Research Foundation,
Sankara Nethralaya, Chennai 600 006, Tamil Nadu, India
| | - Sulochana Konerirajapuram Natarajan
- R.S.
Mehta Jain Department of Biochemistry and Cell Biology, Kamalnayan
Bajaj Institute for Research in Vision and Ophthalmology, Vision Research Foundation, Sankara Nethralaya, Chennai 600 006, Tamil Nadu, India
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Ando F, Matsuda A, Miyashita M, Matsumoto S, Sakurazawa N, Kawano Y, Yoshida H. Placement of a self-expandable metallic stent as a bridge to surgery for large bowel obstruction induced by effective neoadjuvant therapy: report of three cases. Surg Case Rep 2018; 4:100. [PMID: 30141152 PMCID: PMC6107482 DOI: 10.1186/s40792-018-0509-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2018] [Accepted: 08/15/2018] [Indexed: 11/30/2022] Open
Abstract
Background Self-expandable metallic stent placement is a widely performed palliative procedure or bridge to surgery for obstructive colorectal cancer. However, the feasibility of this procedure for large bowel obstruction induced by effective neoadjuvant therapy is unclear. Case presentation We herein report three such cases involving a 61-year-old man who underwent neoadjuvant chemoradiotherapy for lower rectal cancer, a 56-year-old woman who underwent neoadjuvant chemotherapy for lower rectal cancer, and a 63-year-old woman who underwent neoadjuvant chemotherapy for lower rectal cancer. All were emergently hospitalized with large bowel obstruction that developed while undergoing neoadjuvant therapy. Colonoscopy revealed smooth strictures caused by effective neoadjuvant therapy. Self-expandable metallic stents were placed across the obstruction as a bridge to surgery, and laparoscopic low anterior resection was uneventfully performed in all patients. Conclusions We successfully treated three patients with large bowel obstruction induced by a good response to neoadjuvant therapy using self-expandable metallic stents as a bridge to surgery. Further studies with larger sample sizes are warranted to assess the feasibility of this strategy.
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Affiliation(s)
- Fumihiko Ando
- Department of Surgery, Nippon Medical School Chiba Hokusoh Hospital, 1715 Kamagari, Inzai, Chiba, 270-1694, Japan
| | - Akihisa Matsuda
- Department of Surgery, Nippon Medical School Chiba Hokusoh Hospital, 1715 Kamagari, Inzai, Chiba, 270-1694, Japan.
| | - Masao Miyashita
- Department of Surgery, Nippon Medical School Chiba Hokusoh Hospital, 1715 Kamagari, Inzai, Chiba, 270-1694, Japan
| | - Satoshi Matsumoto
- Department of Surgery, Nippon Medical School Chiba Hokusoh Hospital, 1715 Kamagari, Inzai, Chiba, 270-1694, Japan
| | - Nobuyuki Sakurazawa
- Department of Surgery, Nippon Medical School Chiba Hokusoh Hospital, 1715 Kamagari, Inzai, Chiba, 270-1694, Japan
| | - Youichi Kawano
- Department of Surgery, Nippon Medical School Chiba Hokusoh Hospital, 1715 Kamagari, Inzai, Chiba, 270-1694, Japan
| | - Hiroshi Yoshida
- Department of Gastrointestinal and Hepato-Biliary-Pancreatic Surgery, Nippon Medical School, 1-1-5 Sendagi, Bunkyo, Tokyo, 113-8603, Japan
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Li Y, Tan BB, Fan LQ, Zhao Q, Liu Y, Wang D. Heterogeneity of COX-2 and Multidrug Resistance between Primary Tumors and Regional Lymph Node Metastases of Gastric Cancer. TUMORI JOURNAL 2018; 98:516-22. [DOI: 10.1177/030089161209800418] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Aims and background Cyclooxygenase-2 (COX-2) is involved in the progression of gastric cancer; however, the role of COX-2 in multidrug resistance (MDR) is still unclear. This study aimed to elucidate the relationship between COX-2 and MDR so as to show the heterogeneity of gastric primary tumors and regional lymph node metastases. Methods Between 2008 and 2009, 56 primary tumor samples and paired metastatic lymph node tissues from gastric cancer patients confirmed by surgery and pathological examination in our hospital were collected. The expression levels of COX-2 and MDR-associated factors such as P-glycoprotein (P-gp), glutathione S-transferase pi (GST-π) and topoisomerase II alpha (Topo-II-α) were determined by immunohistochemical staining. Tumor cells from these tissues were cultured and the cell chemosensitivities for 11 chemotherapeutic agents were measured by sulforhodamine B assay. Results The expression levels of COX-2, P-gp and GST-π were significantly higher in metastatic lymph node tissues than in primary tumors, while the expression level of Topo-II-α was lower in metastatic lymph node tissues than in primary tumors (all P <0.05). In primary tumors, COX-2 and GST-π were positively correlated and COX-2 and Topo-II-α were negatively correlated; in metastatic lymph node tissues, a positive correlation was found between COX-2 and P-gp (all P <0.05). The inhibition rates of eADM, VP-16, THP and MMC on cells from primary tumors were significantly lower than those on cells from metastatic lymph nodes, while the inhibition rates of HCPT, L-OHP and VCR on cells from metastatic lymph nodes were lower than those on cells from primary tumors. Conclusion The expression of COX-2 and MDR-associated factors as well as cell chemosensitivities are different in primary tumors and regional lymph node metastases of gastric cancer, and this may be an indication of their heterogeneity.
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Affiliation(s)
- Yong Li
- Department of General Surgery, the Fourth Affiliated Hospital, Hebei Medical University, Shijiazhuang, China
| | - Bi-bo Tan
- Department of General Surgery, the Fourth Affiliated Hospital, Hebei Medical University, Shijiazhuang, China
| | - Li-qiao Fan
- Department of General Surgery, the Fourth Affiliated Hospital, Hebei Medical University, Shijiazhuang, China
| | - Qun Zhao
- Department of General Surgery, the Fourth Affiliated Hospital, Hebei Medical University, Shijiazhuang, China
| | - Yü Liu
- Department of General Surgery, the Fourth Affiliated Hospital, Hebei Medical University, Shijiazhuang, China
| | - Dong Wang
- Department of General Surgery, the Fourth Affiliated Hospital, Hebei Medical University, Shijiazhuang, China
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Cheah R, Srivastava R, Stafford ND, Beavis AW, Green V, Greenman J. Measuring the response of human head and neck squamous cell carcinoma to irradiation in a microfluidic model allowing customized therapy. Int J Oncol 2017; 51:1227-1238. [PMID: 28902347 DOI: 10.3892/ijo.2017.4118] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2017] [Accepted: 07/31/2017] [Indexed: 11/06/2022] Open
Abstract
Radiotherapy is the standard treatment for head and neck squamous cell carcinoma (HNSCC), however, radioresistance remains a major clinical problem despite significant improvements in treatment protocols. Therapeutic outcome could potentially be improved if a patient's tumour response to irradiation could be predicted ex vivo before clinical application. The present study employed a bespoke microfluidic device to maintain HNSCC tissue whilst subjecting it to external beam irradiation and measured the responses using a panel of cell death and proliferation markers. HNSCC biopsies from five newly-presenting patients [2 lymph node (LN); 3 primary tumour (PT)] were divided into parallel microfluidic devices and replicates of each tumour were subjected to single-dose irradiation (0, 5, 10, 15 and 20 Gy). Lactate dehydrogenase (LDH) release was measured and tissue sections were stained for cytokeratin (CK), cleaved-CK18 (cCK18), phosphorylated-H2AX (γH2AX) and Ki‑67 by immunohistochemistry. In addition, fragmented DNA was detected using terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL). Compared with non‑irradiated controls, higher irradiation doses resulted in elevated CK18-labelling index in two lymph nodes [15 Gy; 34.8% on LN1 and 31.7% on LN2 (p=0.006)] and a single laryngeal primary tumour (20 Gy; 31.5%; p=0.014). Significantly higher levels of DNA fragmentation were also detected in both lymph node samples and one primary tumour but at varying doses of irradiation, i.e., LN1 (20 Gy; 27.6%; p=0.047), LN2 (15 Gy; 15.3%; p=0.038) and PT3 (10 Gy; 35.2%; p=0.01). The γH2AX expression was raised but not significantly in the majority of samples. The percentage of Ki‑67 positive nuclei reduced dose-dependently following irradiation. In contrast no significant difference in LDH release was observed between irradiated groups and controls. There is clear inter- and intra-patient variability in response to irradiation when measuring a variety of parameters, which offers the potential for the approach to provide clinically valuable information.
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Affiliation(s)
- Ramsah Cheah
- Hull York Medical School, University of Hull, Hull, HU6 7RX, UK
| | | | | | - Andrew W Beavis
- Radiation Physics, Hull and East Yorkshire Hospitals NHS Trust, Faculty of Science and Engineering, University of Hull, Hull, HU6 7RX, UK
| | - Victoria Green
- School of Life Sciences, University of Hull, Hull, HU6 7RX, UK
| | - John Greenman
- School of Life Sciences, University of Hull, Hull, HU6 7RX, UK
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7
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Santos MD, Silva C, Rocha A, Nogueira C, Castro-Poças F, Araujo A, Matos E, Pereira C, Medeiros R, Lopes C. Predictive clinical model of tumor response after chemoradiation in rectal cancer. Oncotarget 2017; 8:58133-58151. [PMID: 28938543 PMCID: PMC5601639 DOI: 10.18632/oncotarget.19651] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2017] [Accepted: 07/18/2017] [Indexed: 12/25/2022] Open
Abstract
Survival improvement in rectal cancer treated with neoadjuvant chemoradiotherapy (nCRT) is achieved only if pathological response occurs. Mandard tumor regression grade (TRG) proved to be a valid system to measure nCRT response. The ability to predict tumor response before treatment may significantly have impact the selection of patients for nCRT in rectal cancer. The aim is to identify potential predictive pretreatment factors for Mandard response and build a clinical predictive model design. 167 patients with locally advanced rectal cancer were treated with nCRT and curative surgery. Blood cell counts in peripheral blood were analyzed. Pretreatment biopsies expression of cyclin D1, epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF) and protein 21 were assessed. A total of 61 single nucleotide polymorphisms were characterized using the Sequenom platform through multiplex amplification followed by mass-spectometric product separation. Surgical specimens were classified according to Mandard TRG. The patients were divided as: "good responders" (Mandard TRG1-2) and "poor responders" (Mandard TGR3-5). We examined predictive factors for Mandard response and performed statistical analysis. In univariate analysis, distance from anal verge, neutrophil lymphocyte ratio (NLR), cyclin D1, VEGF, EGFR, protein 21 and rs1810871 interleukin 10 (IL10) gene polymorphism are the pretreatment variables with predictive value for Mandard response. In multivariable analysis, NLR, cyclin D1, protein 21 and rs1800871 in IL10 gene maintain predictive value, allowing a clinical model design. CONCLUSION It seems possible to use pretreatment expression of blood and tissue biomarkers, and build a model of tumor response prediction to neoadjuvant chemoradiation in rectal cancer.
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Affiliation(s)
- Marisa D Santos
- Department of Surgery, Digestive Surgery Service, Hospital Center of Porto, Porto, Portugal.,Abel Salazar Biomedical Science Institute, University of Porto, Porto, Portugal
| | - Cristina Silva
- Department of Surgery, Digestive Surgery Service, Hospital Center of Porto, Porto, Portugal.,Abel Salazar Biomedical Science Institute, University of Porto, Porto, Portugal
| | - Anabela Rocha
- Department of Surgery, Digestive Surgery Service, Hospital Center of Porto, Porto, Portugal.,Abel Salazar Biomedical Science Institute, University of Porto, Porto, Portugal
| | - Carlos Nogueira
- Department of Surgery, Digestive Surgery Service, Hospital Center of Porto, Porto, Portugal.,Abel Salazar Biomedical Science Institute, University of Porto, Porto, Portugal
| | - Fernando Castro-Poças
- Abel Salazar Biomedical Science Institute, University of Porto, Porto, Portugal.,Gastroenterology Service, Hospital Center of Porto, Porto, Portugal
| | - António Araujo
- Abel Salazar Biomedical Science Institute, University of Porto, Porto, Portugal.,Service of Medical Oncology, Hospital Center of Porto, Porto, Portugal
| | - Eduarda Matos
- Department of Health Community, Abel Salazar Biomedical Science Institute, University of Porto, Porto, Portugal
| | - Carina Pereira
- Abel Salazar Biomedical Science Institute, University of Porto, Porto, Portugal.,Molecular Oncology and Viral Pathology Group, IPO Research Center, Portuguese Oncologic Institute, Porto, Portugal.,Research Department, Portuguese League Against Cancer, Porto, Portugal
| | - Rui Medeiros
- Abel Salazar Biomedical Science Institute, University of Porto, Porto, Portugal.,Molecular Oncology and Viral Pathology Group, IPO Research Center, Portuguese Oncologic Institute, Porto, Portugal.,Research Department, Portuguese League Against Cancer, Porto, Portugal.,CEBIMED, Faculty of Health Sciences of Fernando Pessoa, University of Porto, Porto, Portugal
| | - Carlos Lopes
- Abel Salazar Biomedical Science Institute, University of Porto, Porto, Portugal.,Department of Pathology, Pathological Anatomy Service, Hospital Center of Porto, Porto, Portugal.,Department of Pathology and Molecular Immunology, Abel Salazar Biomedical Science Institute, University of Porto, Porto, Portugal
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8
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Li P, Xiao ZT, Braciak TA, Ou QJ, Chen G, Oduncu FS. Association between Ki67 Index and Clinicopathological Features in Colorectal Cancer. Oncol Res Treat 2016; 39:696-702. [PMID: 27855388 DOI: 10.1159/000450623] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2016] [Accepted: 08/30/2016] [Indexed: 11/19/2022]
Abstract
BACKGROUND Conflicting results have been reported about the association between the Ki67 labeling index (Ki67-Li) and clinical outcome in patients with colorectal cancer (CRC). PATIENTS AND METHODS Ki67 expression was assessed by immunohistochemistry (IHC) in 2,233 consecutive CRC cases. RESULTS We determined 992 cases to have a low and 1,241 cases to have a high Ki67-Li (representing an approximately 44-56% breakdown in distribution between low versus high patients designated by phenotype). Stage III patients with a high Ki67-Li had higher 3-year disease-free survival (DFS) and overall survival (OS) than those with a low Ki67-Li (DFS 70 vs. 61%; p = 0.02 and OS 75 vs. 64%; p = 0.008). We also found significantly improved 3-year progression-free survival (PFS) for stage IV patients in the high versus the low Ki67-Li group (PFS 14 vs. 10%; p = 0.02). Yet, we found no statistical differences in prognosis for stage I and II patients and in OS for stage IV patients between high versus low Ki67-Li (p > 0.05). CONCLUSION Our results suggest that high Ki67-Li can be an independent prognostic biomarker to aid the assessment of patient outcomes in both stage III and IV CRC.
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Affiliation(s)
- Pan Li
- Department of Hematology and Oncology, Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Munich, Germany
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van Kuijk SJA, Yaromina A, Houben R, Niemans R, Lambin P, Dubois LJ. Prognostic Significance of Carbonic Anhydrase IX Expression in Cancer Patients: A Meta-Analysis. Front Oncol 2016; 6:69. [PMID: 27066453 PMCID: PMC4810028 DOI: 10.3389/fonc.2016.00069] [Citation(s) in RCA: 105] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2015] [Accepted: 03/08/2016] [Indexed: 01/08/2023] Open
Abstract
Hypoxia is a characteristic of many solid tumors and an adverse prognostic factor for treatment outcome. Hypoxia increases the expression of carbonic anhydrase IX (CAIX), an enzyme that is predominantly found on tumor cells and is involved in maintaining the cellular pH balance. Many clinical studies investigated the prognostic value of CAIX expression, but most have been inconclusive, partly due to small numbers of patients included. The present meta-analysis was therefore performed utilizing the results of all clinical studies to determine the prognostic value of CAIX expression in solid tumors. Renal cell carcinoma was excluded from this meta-analysis due to an alternative mechanism of upregulation. 958 papers were identified from a literature search performed in PubMed and Embase. These papers were independently evaluated by two reviewers and 147 studies were included in the analysis. The meta-analysis revealed strong significant associations between CAIX expression and all endpoints: overall survival [hazard ratio (HR) = 1.76, 95% confidence interval (95%CI) 1.58–1.98], disease-free survival (HR = 1.87, 95%CI 1.62–2.16), locoregional control (HR = 1.54, 95%CI 1.22–1.93), disease-specific survival (HR = 1.78, 95%CI 1.41–2.25), metastasis-free survival (HR = 1.82, 95%CI 1.33–2.50), and progression-free survival (HR = 1.58, 95%CI 1.27–1.96). Subgroup analyses revealed similar associations in the majority of tumor sites and types. In conclusion, these results show that patients having tumors with high CAIX expression have higher risk of locoregional failure, disease progression, and higher risk to develop metastases, independent of tumor type or site. The results of this meta-analysis further support the development of a clinical test to determine patient prognosis based on CAIX expression and may have important implications for the development of new treatment strategies.
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Affiliation(s)
- Simon J A van Kuijk
- Department of Radiation Oncology (MAASTRO Lab), GROW - School for Oncology and Developmental Biology, Maastricht University Medical Centre , Maastricht , Netherlands
| | - Ala Yaromina
- Department of Radiation Oncology (MAASTRO Lab), GROW - School for Oncology and Developmental Biology, Maastricht University Medical Centre , Maastricht , Netherlands
| | - Ruud Houben
- Department of Radiation Oncology, MAASTRO Clinic , Maastricht , Netherlands
| | - Raymon Niemans
- Department of Radiation Oncology (MAASTRO Lab), GROW - School for Oncology and Developmental Biology, Maastricht University Medical Centre , Maastricht , Netherlands
| | - Philippe Lambin
- Department of Radiation Oncology (MAASTRO Lab), GROW - School for Oncology and Developmental Biology, Maastricht University Medical Centre , Maastricht , Netherlands
| | - Ludwig J Dubois
- Department of Radiation Oncology (MAASTRO Lab), GROW - School for Oncology and Developmental Biology, Maastricht University Medical Centre , Maastricht , Netherlands
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Hav M, Libbrecht L, Ferdinande L, Geboes K, Pattyn P, Cuvelier CA. Pathologic Assessment of Rectal Carcinoma after Neoadjuvant Radio(chemo)therapy: Prognostic Implications. BIOMED RESEARCH INTERNATIONAL 2015; 2015:574540. [PMID: 26509160 PMCID: PMC4609786 DOI: 10.1155/2015/574540] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/28/2015] [Accepted: 06/14/2015] [Indexed: 12/21/2022]
Abstract
Neoadjuvant radio(chemo)therapy is increasingly used in rectal cancer and induces a number of morphologic changes that affect prognostication after curative surgery, thereby creating new challenges for surgical pathologists, particularly in evaluating morphologic changes and tumour response to preoperative treatment. Surgical pathologists play an important role in determining the many facets of rectal carcinoma patient care after neoadjuvant treatment. These range from proper handling of macroscopic specimens to accurate microscopic evaluation of pathological features associated with patients' prognosis. This review presents the well-established pathological prognostic indicators and discusses challenging features in order to provide both surgical pathologists and treating physicians with a checklist that is useful in a neoadjuvant setting.
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Affiliation(s)
- Monirath Hav
- Department of Pathology, Calmette Hospital, No. 3, Monivong Boulevard (93), Phnom Penh 12201, Cambodia ; Department of Pathology, Ghent University Hospital, 9000 Gent, Belgium
| | - Louis Libbrecht
- Department of Pathology, Calmette Hospital, No. 3, Monivong Boulevard (93), Phnom Penh 12201, Cambodia
| | - Liesbeth Ferdinande
- Department of Pathology, Calmette Hospital, No. 3, Monivong Boulevard (93), Phnom Penh 12201, Cambodia
| | - Karen Geboes
- Department of Gastrointestinal Oncology, Ghent University Hospital, 9000 Gent, Belgium
| | - Piet Pattyn
- Department of Gastrointestinal Surgery, Ghent University Hospital, 9000 Gent, Belgium
| | - Claude A Cuvelier
- Department of Pathology, Calmette Hospital, No. 3, Monivong Boulevard (93), Phnom Penh 12201, Cambodia
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Patel PM, Harris K, Huerta S. Clinical and molecular diagnosis of pathologic complete response in rectal cancer. Expert Rev Mol Diagn 2015; 15:1505-16. [DOI: 10.1586/14737159.2015.1091728] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
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Predictive and prognostic biomarkers for neoadjuvant chemoradiotherapy in locally advanced rectal cancer. Crit Rev Oncol Hematol 2015; 96:67-80. [PMID: 26032919 DOI: 10.1016/j.critrevonc.2015.05.003] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2014] [Revised: 03/03/2015] [Accepted: 05/05/2015] [Indexed: 02/08/2023] Open
Abstract
Locally advanced rectal cancer is regularly treated with trimodality therapy consisting of neoadjuvant chemoradiation, surgery and adjuvant chemotherapy. There is a need for biomarkers to assess treatment response, and aid in stratification of patient risk to adapt and personalise components of the therapy. Currently, pathological stage and tumour regression grade are used to assess response. Experimental markers include proteins involved in cell proliferation, apoptosis, angiogenesis, the epithelial to mesenchymal transition and microsatellite instability. As yet, no single marker is sufficiently robust to have clinical utility. Microarrays that screen a tumour for multiple promising candidate markers, gene expression and microRNA profiling will likely have higher yield and it is expected that a combination or panel of markers would prove most useful. Moving forward, utilising serial samples of circulating tumour cells or circulating nucleic acids can potentially allow us to demonstrate tumour heterogeneity, document mutational changes and subsequently measure treatment response.
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Hav M, Libbrecht L, Geboes K, Ferdinande L, Boterberg T, Ceelen W, Pattyn P, Cuvelier C. Prognostic value of tumor shrinkage versus fragmentation following radiochemotherapy and surgery for rectal cancer. Virchows Arch 2015; 466:517-23. [PMID: 25693669 DOI: 10.1007/s00428-015-1723-x] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2014] [Revised: 01/04/2015] [Accepted: 01/20/2015] [Indexed: 12/19/2022]
Abstract
Most patients with rectal cancer receive neoadjuvant radiochemotherapy (RCT), causing a variable decrease in tumor mass. We evaluated the prognostic impact of pathologic parameters reflecting tumor response to RCT, either directly or indirectly. Seventy-six rectal cancer patients receiving neoadjuvant RCT between 2006 and 2009 were included. We studied the association between disease-free survival (DFS) and the "classical" clinicopathologic features as well as tumor deposits, circumferential resection margin (CRM), Dworak regression grade, and tumor and nodal downstaging. Patients with tumor downstaging had a longer DFS (p = 0.05), indicating a more favorable prognosis when regression was accompanied by a decrease in tumor infiltrative depth, referred to as tumor shrinkage. Moreover, tumor downstaging was significantly associated with larger CRM and nodal downstaging (p = 0.02), suggesting that shrinkage of the primary tumor was associated with a decreased nodal tumor load. Higher Dworak grade did not correlate with tumor downstaging, nor with higher CRM or prolonged DFS. This implies that tumor mass decrease was sometimes due to fragmentation rather than shrinkage of the primary tumor. Lastly, the presence of tumor deposits was clearly associated with reduced DFS (p = 0.01). Assessment of tumor shrinkage after RCT via tumor downstaging and CRM is a good way of predicting DFS in rectal cancer, and shrinkage of the primary tumor is associated with a decreased nodal tumor load. Assessing regression based on the amount of tumor in relation to stromal fibrosis does not accurately discern tumor fragmentation from tumor shrinkage, which is most likely the reason why Dworak grade had less prognostic relevance.
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Affiliation(s)
- Monirath Hav
- Department of Pathology, Calmette Hospital, #3, Monivong Boulevard, Phnom Penh, Cambodia,
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Dzhugashvili M, Luengo-Gil G, García T, González-Conejero R, Conesa-Zamora P, Escolar PP, Calvo F, Vicente V, Ayala de la Peña F. Role of genetic polymorphisms in NFKB-mediated inflammatory pathways in response to primary chemoradiation therapy for rectal cancer. Int J Radiat Oncol Biol Phys 2014; 90:595-602. [PMID: 25304949 DOI: 10.1016/j.ijrobp.2014.06.060] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2014] [Revised: 05/20/2014] [Accepted: 06/23/2014] [Indexed: 12/20/2022]
Abstract
PURPOSE To investigate whether polymorphisms of genes related to inflammation are associated with pathologic response (primary endpoint) in patients with rectal cancer treated with primary chemoradiation therapy (PCRT). METHODS AND MATERIALS Genomic DNA of 159 patients with locally advanced rectal cancer treated with PCRT was genotyped for polymorphisms rs28362491 (NFKB1), rs1213266/rs5789 (PTGS1), rs5275 (PTGS2), and rs16944/rs1143627 (IL1B) using TaqMan single nucleotide polymorphism genotyping assays. The association between each genotype and pathologic response (poor response vs complete or partial response) was analyzed using logistic regression models. RESULTS The NFKB1 DEL/DEL genotype was associated with pathologic response (odds ratio [OR], 6.39; 95% confidence interval [CI], 0.78-52.65; P=.03) after PCRT. No statistically significant associations between other polymorphisms and response to PCRT were observed. Patients with the NFKB1 DEL/DEL genotype showed a trend for longer disease-free survival (log-rank test, P=.096) and overall survival (P=.049), which was not significant in a multivariate analysis that included pathologic response. Analysis for 6 polymorphisms showed that patients carrying the haplotype rs28362491-DEL/rs1143627-A/rs1213266-G/rs5789-C/rs5275-A/rs16944-G (13.7% of cases) had a higher response rate to PCRT (OR, 8.86; 95% CI, 1.21-64.98; P=.034) than the reference group (rs28362491-INS/rs1143627-A/rs1213266-G/rs5789-C/rs5275-A/rs16944-G). Clinically significant (grade ≥2) acute organ toxicity was also more frequent in patients with that same haplotype (OR, 4.12; 95% CI, 1.11-15.36; P=.037). CONCLUSIONS Our results suggest that genetic variation in NFKB-related inflammatory pathways might influence sensitivity to primary chemoradiation for rectal cancer. If confirmed, an inflammation-related radiogenetic profile might be used to select patients with rectal cancer for preoperative combined-modality treatment.
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Affiliation(s)
- Maia Dzhugashvili
- Department of Hematology and Medical Oncology, University Hospital Morales Meseguer, Murcia, Spain; Department of Radiation Oncology, Madrid Oncology Institute (Group IMO), Murcia, Spain
| | - Ginés Luengo-Gil
- Department of Hematology and Medical Oncology, University Hospital Morales Meseguer, Murcia, Spain
| | - Teresa García
- Department of Hematology and Medical Oncology, University Hospital Morales Meseguer, Murcia, Spain
| | - Rocío González-Conejero
- Department of Hematology and Medical Oncology, University Hospital Morales Meseguer, Murcia, Spain
| | | | - Pedro Pablo Escolar
- Department of Radiation Oncology, University Hospital Santa Lucía, Cartagena, Spain
| | - Felipe Calvo
- Department of Radiation Oncology, University General Hospital Gregorio Marañón, Madrid, Spain
| | - Vicente Vicente
- Department of Hematology and Medical Oncology, University Hospital Morales Meseguer, Murcia, Spain
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Ramzan Z, Nassri AB, Huerta S. Genotypic characteristics of resistant tumors to pre-operative ionizing radiation in rectal cancer. World J Gastrointest Oncol 2014; 6:194-210. [PMID: 25024812 PMCID: PMC4092337 DOI: 10.4251/wjgo.v6.i7.194] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2013] [Revised: 03/19/2014] [Accepted: 05/08/2014] [Indexed: 02/05/2023] Open
Abstract
Due to a wide range of clinical response in patients undergoing neo-adjuvant chemoradiation for rectal cancer it is essential to understand molecular factors that lead to the broad response observed in patients receiving the same form of treatment. Despite extensive research in this field, the exact mechanisms still remain elusive. Data raging from DNA-repair to specific molecules leading to cell survival as well as resistance to apoptosis have been investigated. Individually, or in combination, there is no single pathway that has become clinically applicable to date. In the following review, we describe the current status of various pathways that might lead to resistance to the therapeutic applications of ionizing radiation in rectal cancer.
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Koskensalo S, Louhimo J, Hagström J, Lundin M, Stenman UH, Haglund C. Concomitant tumor expression of EGFR and TATI/SPINK1 associates with better prognosis in colorectal cancer. PLoS One 2013; 8:e76906. [PMID: 24204699 PMCID: PMC3808372 DOI: 10.1371/journal.pone.0076906] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2013] [Accepted: 08/29/2013] [Indexed: 02/06/2023] Open
Abstract
Background Epidermal growth factor receptor (EGFR) activation plays a role in colorectal cancer (CRC) carcinogenesis, and anti-EGFR drugs are used in treatment of advanced CRC. One of the EGFR ligands is tumor-associated trypsinogen inhibitor TATI, also called serine protease inhibitor Kazal type1 (SPINK 1), which we recently showed to be an independent prognostic marker in CRC. Methods We studied the prognostic value of immunohistochemical expression of EGFR and concomitant expression of EGFR and TATI/SPINK1 in a series of 619 colorectal cancer patients. Results Of the samples, 92% were positive for EGFR. EGFR+/TATI+ was seen in 62.8%, EGFR+/TATI− in 29.5%, EGFR−/TATI+ in 4.9%, and EGFR−/TATI− in 2.7% of patients. EGFR expression correlated with WHO grade (p = 0.040). In univariate analysis, EGFR expression correlated with favourable survival (p = 0.006). EGFR+/TATI+ patients showed better survival than did those with other combinations (p<0.001). In multivariate analysis, EGFR+/TATI+ was an independent prognostic factor of favourable prognosis (p<0.001). Conclusion Concomitant positivity of EGFR and TATI/SPINK1 predicts favourable prognosis in CRC.
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Affiliation(s)
- Selja Koskensalo
- Department of Surgery, Helsinki University Central Hospital, Helsinki, Finland
| | - Johanna Louhimo
- Department of Surgery, Helsinki University Central Hospital, Helsinki, Finland
| | - Jaana Hagström
- Department of Pathology, Haartman Institute, University of Helsinki, Helsinki, Finland
| | - Mikael Lundin
- Finnish Institution of Molecular Medicine Helsinki, University of Helsinki, Helsinki, Finland
| | - Ulf-Håkan Stenman
- Department of Clinical Chemistry, Helsinki University Central Hospital, Helsinki, Finland
| | - Caj Haglund
- Department of Surgery, Helsinki University Central Hospital, Helsinki, Finland
- Department of Pathology, Haartman Institute, University of Helsinki, Helsinki, Finland
- Research Programs Unit, Translational Cancer Biology, University of Helsinki, Helsinki, Finland
- * E-mail:
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Torino F, Sarmiento R, Gasparini G. The contribution of targeted therapy to the neoadjuvant chemoradiation of rectal cancer. Crit Rev Oncol Hematol 2013; 87:283-305. [DOI: 10.1016/j.critrevonc.2013.02.002] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2012] [Revised: 12/24/2012] [Accepted: 02/13/2013] [Indexed: 12/26/2022] Open
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Kykalos S, Dimitroulis D, Ntikoudi E, Karayiannakis A. The clinical significance of apoptosis and M30 expression in colonic cancer progression. J Recept Signal Transduct Res 2013; 33:255-9. [DOI: 10.3109/10799893.2013.802804] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
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Peng L, Zhou Y, Wang Y, Mou H, Zhao Q. Prognostic significance of COX-2 immunohistochemical expression in colorectal cancer: a meta-analysis of the literature. PLoS One 2013; 8:e58891. [PMID: 23527044 PMCID: PMC3604072 DOI: 10.1371/journal.pone.0058891] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2012] [Accepted: 02/07/2013] [Indexed: 12/15/2022] Open
Abstract
Background Cyclooxygenase-2 (COX-2) is believed to be an important enzyme in the pathogenesis of colorectal cancer (CRC). Correlations between the expression of COX-2 with tumor growth and distant metastasis have become an issue; thus, attention has been paid to COX-2 as a prognostic factor. Various studies examined the relationship between COX-2 immunohistochemistry (IHC) overexpression with the clinical outcome in patients with colorectal cancer, but yielded conflicting results. The prognostic significance of COX-2 overexpression in colorectal cancer remains controversial. Methods Electronic databases updated to October 2012 were searched to find relevant studies. A meta-analysis was conducted with eligible studies which quantitatively evaluated the relationship between COX-2 overexpression and survival of patients with colorectal cancer. Survival data were aggregated and quantitatively analyzed. Results We performed a meta-analysis of 23 studies (n = 4567 patients) that evaluated the correlation between COX-2 overexpression detected by IHC and survival in patients with colorectal cancer. Combined hazard ratios suggested that COX-2 overexpression had an unfavorable impact on overall survival (OS) (HR [hazard ratio] = 1.193, 95% CI [confidence interval]: 1.02 ∼ 1.37), but not disease free survival (DFS) (HR = 1.25, 95% CI: 0.99 ∼ 1.50) in patients with colorectal cancer. Conclusions Cox-2 overexpression in colorectal cancer detected by IHC appears to have slightly worse overall survival. However, the prognostic value of COX-2 on survival in colorectal cancer still needs further large-scale prospective trials to be clarified.
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Affiliation(s)
- Ling Peng
- Department of Thoracic Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Yun Zhou
- Zhejiang Food and Drug Administration, Hangzhou, China
| | - Yina Wang
- Department of Thoracic Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Haibo Mou
- Department of Thoracic Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Qiong Zhao
- Department of Thoracic Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- * E-mail:
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McDonald PC, Winum JY, Supuran CT, Dedhar S. Recent developments in targeting carbonic anhydrase IX for cancer therapeutics. Oncotarget 2012; 3:84-97. [PMID: 22289741 PMCID: PMC3292895 DOI: 10.18632/oncotarget.422] [Citation(s) in RCA: 329] [Impact Index Per Article: 25.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Carbonic anhydrase IX (CAIX) is a hypoxia-inducible enzyme that is overexpressed by cancer cells from many tumor types, and is a component of the pH regulatory system invoked by these cells to combat the deleterious effects of a high rate of glycolytic metabolism. CAIX functions to help produce and maintain an intracellular pH (pHi) favorable for tumor cell growth and survival, while at the same time participating in the generation of an increasingly acidic extracellular space, facilitating tumor cell invasiveness. Pharmacologic interference of CAIX catalytic activity using monoclonal antibodies or CAIX-specific small molecule inhibitors, consequently disrupting pH regulation by cancer cells, has been shown recently to impair primary tumor growth and metastasis. Many of these agents are in preclinical or clinical development and constitute a novel, targeted strategy for cancer therapy.
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Affiliation(s)
- Paul C McDonald
- Department of Integrative Oncology, British Columbia Cancer Research Centre and Cancer Agency, Vancouver, BC, Canada
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Avoranta ST, Korkeila EA, Minn HRI, Syrjänen KJ, Pyrhönen SO, Sundström JTT. Securin identifies a subgroup of patients with poor outcome in rectal cancer treated with long-course (chemo)radiotherapy. Acta Oncol 2011; 50:1158-66. [PMID: 22023115 DOI: 10.3109/0284186x.2011.584327] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
BACKGROUND Securin is an oncogene with functions in cell proliferation, tumour initiation and progression. Its prognostic value in rectal cancer is somewhat unknown. Accordingly, we studied securin expression together with Ki-67 in rectal cancer in relation to preoperative (chemo)radiotherapy (RT) and disease outcome. MATERIAL AND METHODS Biopsies (n = 65 for securin; n = 57 for Ki-67) and operative specimens (n = 207) from 211 patients treated with short-course RT (n = 87), long-course RT (n = 54) or surgery only (n = 70) were studied with immunohistochemistry (IHC) for securin and Ki-67 expression. In the long-course RT group, 45 patients received chemotherapy (5-fluorouracil or capecitabine) concomitantly with RT. The results of IHC were related to clinicopathological variables, disease outcome and tumour regression grade (TRG) after long-course RT. RESULTS Both markers showed significant reduction after RT (p < 0.001). No differences in expression was seen in the long-course RT group between the patients with or without concomitant chemotherapy (p = 0.23 for securin; p = 0.31 for Ki-67). Low Ki-67 expression, but not that of securin, in operative specimens was significantly related to excellent TRG (p = 0.02 for Ki-67; p = 0.21 for securin). In univariate survival analysis, excellent TRG predicted longer disease-specific survival (DSS; p = 0.03). In multivariate Cox analysis, high securin expression after long-course (chemo)RT was an independent predictor of shorter DSS (p = 0.036) together with patient age (p = 0.043) and disease recurrence (local or distant; p = 0.009), whereas no similar appearance was seen in other treatment groups. CONCLUSION Securin expression in rectal cancer is significantly reduced after RT. High securin expression and poor TRG after long-course (chemo)RT are indicators of unfavourable disease outcome.
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Affiliation(s)
- S Tuulia Avoranta
- Department of Oncology and Radiotherapy, University of Turku, Turku University Hospital, Finland.
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22
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Yeung JMC, Kalff V, Hicks RJ, Drummond E, Link E, Taouk Y, Michael M, Ngan S, Lynch AC, Heriot AG. Metabolic response of rectal cancer assessed by 18-FDG PET following chemoradiotherapy is prognostic for patient outcome. Dis Colon Rectum 2011; 54:518-25. [PMID: 21471751 DOI: 10.1007/dcr.0b013e31820b36f0] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
BACKGROUND Complete pathological response has proven prognostic benefits in patients with locally advanced rectal cancer treated with neoadjuvant chemoradiotherapy. Sequential 18-FDG PET may be an early surrogate for pathological response to chemoradiotherapy. OBJECTIVES The aim of this study was to identify whether metabolic response measured by FDG PET following chemoradiotherapy is prognostic for tumor recurrence and survival following neoadjuvant therapy and surgical treatment for primary rectal cancer. METHODS Patients with primary rectal cancer treated by long-course neoadjuvant chemoradiotherapy followed by surgery had FDG PET performed before and 4 weeks after treatment, before surgical resection was performed. Retrospective chart review was undertaken for patient demographics, tumor staging, recurrence rates, and survival. RESULTS : Between 2000 and 2007, 78 patients were identified (53 male, 25 female; median age, 64 y). After chemoradiotherapy, 37 patients (47%) had a complete metabolic response, 26 (33%) had a partial metabolic response, and 14 (18%) had no metabolic response as assessed by FDG PET (1 patient had missing data). However, only 4 patients (5%) had a complete pathological response. The median postoperative follow-up period was 3.1 years during which 14 patients (19%) had a recurrence: 2 local, 9 distant, and 3 with both local and distant. The estimated percentage without recurrence was 77% at 5 years (95% CI 66%-89%). There was an inverse relationship between FDG PET metabolic response and the incidence of recurrence within 3 years (P = .04). Kaplan-Meier analysis of FDG PET metabolic response and overall survival demonstrated a significant difference in survival among patients in the 3 arms: complete, partial, and no metabolic response (P = .04); the patients with complete metabolic response had the best prognosis. CONCLUSION Complete or partial metabolic response on PET following neoadjuvant chemoradiotherapy and surgery predicts a lower local recurrence rate and improved survival compared with patients with no metabolic response. Metabolic response may be used to stratify prognosis in patients with rectal cancer.
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Affiliation(s)
- J M C Yeung
- Department of Surgical Oncology, Peter MacCallum Cancer Centre, St. Andrew's Place, East Melbourne, Victoria, Australia
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Moureau-Zabotto L, Farnault B, de Chaisemartin C, Esterni B, Lelong B, Viret F, Giovannini M, Monges G, Delpero JR, Bories E, Turrini O, Viens P, Salem N. Predictive factors of tumor response after neoadjuvant chemoradiation for locally advanced rectal cancer. Int J Radiat Oncol Biol Phys 2010; 80:483-91. [PMID: 21093174 DOI: 10.1016/j.ijrobp.2010.02.025] [Citation(s) in RCA: 61] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2009] [Revised: 01/15/2010] [Accepted: 02/12/2010] [Indexed: 12/21/2022]
Abstract
PURPOSE Neoadjuvant chemoradiation followed by surgery is the standard of care for locally advanced rectal cancer. The aim of this study was to correlate tumor response to survival and to identify predictive factors for tumor response after chemoradiation. METHODS AND MATERIALS From 1998 to 2008, 168 patients with histologically proven locally advanced adenocarcinoma treated by preoperative chemoradiation before total mesorectal excision were retrospectively studied. They received a radiation dose of 45 Gy with a concomitant 5-fluorouracil (5-FU)-based chemotherapy. Analysis of tumor response was based on lowering of the T stage between pretreatment endorectal ultrasound and pathologic specimens. Overall and progression-free survival rates were correlated with tumor response. Tumor response was analyzed with predictive factors. RESULTS The median follow-up was 34 months. Five-year disease-free survival and overall survival rates were, of 44.4% and 74.5% in the whole population, 83.4% and 83.4%, respectively, in patients with pathological complete response, 38.6% and 71.9%, respectively, in patients with tumor downstaging, and 29.1 and 58.9% respectively, in patients with absence of response. A pretreatment carcinoembryonic antigen (CEA) level of <5 ng/ml was significantly independently associated with pathologic complete tumor response (p = 0.019). Pretreatment small tumor size (p = 0.04), pretreatment CEA level of <5 ng/ml (p = 0.008), and chemotherapy with capecitabine (vs. 5-FU) (p = 0.04) were significantly associated with tumor downstaging. CONCLUSIONS Downstaging and complete response after CRT improved progression-free survival and overall survival of locally advanced rectal adenocarcinoma. In multivariate analysis, a pretreatment CEA level of <5 ng/ml was associated with complete tumor response. Thus, small tumor size, a pretreatment CEA level of < 5 ng/ml, and use of capecitabine were associated with tumor downstaging.
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Huerta S, Hrom J, Gao X, Saha D, Anthony T, Reinhart H, Kapur P. Tissue microarray constructs to predict a response to chemoradiation in rectal cancer. Dig Liver Dis 2010; 42:679-84. [PMID: 20227932 DOI: 10.1016/j.dld.2010.02.003] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2009] [Revised: 01/26/2010] [Accepted: 02/02/2010] [Indexed: 12/11/2022]
Abstract
PURPOSE To identify, using tissue microarray (TMA), an immunohistochemical panel predictive of response to ionizing radiation (IR) in rectal cancer. METHODS TMA constructs were prepared from archived stage II/III rectal tumors and matching adjacent mucosa (n=38) from patients treated with pre-operative chemoradiation. Immunohistochemistry (IHC) was performed for MIB, Cyclin E, p21, p27, p53, survivin, Bcl-2, and BAX. Immunoreactivity along with clinical variables was subjected to univariate and forward stepwise logistic regression analyses. RESULTS Pathological complete response (pCR) was 23.9%. The number of positive lymph nodes obtained in the resected specimen was associated with pCR. Immunoreactivity for MIB (Sn 15%, Sp 65%, OR 0.33), p53 (Sn 3%, Sp 84%, OR 0.16), Bcl-2 (Sn 11%, Sp 74%, OR 0.35), and BAX (Sn 92%, Sp 80%, OR 46) was associated with pathological response (all p's<0.001). Forward stepwise logistic regression analysis demonstrated that MIB was an independent predictor of a response to chemoradiation (p=0.001). CONCLUSIONS A combined panel of mediators of apoptosis alone or combined with clinical factors is a feasible approach that can be applied to rectal tumor biopsies to predict a response to chemoradiation. The most sensitive factor was BAX; while MIB independently predicted a response to chemoradiation.
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Affiliation(s)
- Sergio Huerta
- Department of Surgery, University of Texas Southwestern Medical Center, United States.
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25
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Pang LY, Argyle D. Cancer stem cells and telomerase as potential biomarkers in veterinary oncology. Vet J 2010; 185:15-22. [PMID: 20580998 DOI: 10.1016/j.tvjl.2010.04.008] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Despite advances in chemotherapy and radiotherapy, cancer remains a disease of high morbidity and mortality in domestic animals. In parallel to the development of novel therapeutic interventions, appropriate biomarkers are required to detect early-stage disease and disease remission and relapse at both gross and molecular levels, and the effectiveness of therapy. The field of cancer pathogenesis has grown exponentially over the last decade, both in terms of our understanding of the underlying molecular events, and the technologies available to interrogate the cancer cell. This paper reviews the role of the telomerase enzyme and of telomere length as potential biomarkers in cancer. Furthermore, the potential role of cancer stem cells as biomarkers of malignancy and disease progression is assessed.
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Affiliation(s)
- Lisa Y Pang
- Royal (Dick) School of Veterinary Studies and Roslin Institute, University of Edinburgh Hospital for Small Animals, Easter Bush, Midlothian EH25 9RG, UK
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