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Original Articles
Gastrointestinal cancer
Distinct Characteristics and Changes in Liver Function of Patients with Hepatocellular Carcinoma Treated with Atezolizumab Plus Bevacizumab for More Than 1 Year
Youngun Kim, Jung Sun Kim, Beodeul Kang, Ilhwan Kim, Hyeyeong Kim, Won Suk Lee, Yun Beom Sang, Sanghoon Jung, Chansik An, Chan Kim, Hong Jae Chon
Cancer Res Treat. 2024;56(4):1231-1239.   Published online May 27, 2024
DOI: https://doi.org/10.4143/crt.2024.237
AbstractAbstract PDFSupplementary MaterialPubReaderePub
Purpose
Since 2020, atezolizumab plus bevacizumab (Ate/Bev) has been the standard first-line therapy for unresectable hepatocellular carcinoma (HCC), but long-term treatment studies are limited. This study evaluated the clinical characteristics and effects of Ate/Bev for over 1 year.
Materials and Methods
This study included patients with unresectable HCC treated with first-line Ate/Bev between May 2020 and April 2022. Those receiving Ate/Bev for 1 year or more were classified as the long-term treatment group.
Results
Of 246 patients, 69 (28.0%) were in the long-term treatment group, which comprised more proportions of intrahepatic tumor burden < 25%, Eastern Cooperative Oncology Group 0, and a lower proportion of portal vein tumor thrombosis than the short-term treatment group. The long-term treatment group had a higher incidence of atezolizumab-related thyroid dysfunction (31.9% vs. 10.7%, p < 0.001; median time to onset [mTTO], 2.8 months), dermatologic toxicity (29.0% vs. 14.7%, p=0.017; mTTO, 3.3 months), bevacizumab-related hypertension (44.9% vs. 22.0%, p=0.001; mTTO, 4.2 months), and proteinuria (69.6% vs. 38.4%, p < 0.001; mTTO, 6.8 months), compared to the short-term treatment group. Regarding liver function in the long-term treatment group, patients initially classified as Child-Pugh class A decreased from 87.0% to 75.4%, and albumin-bilirubin grade 1 decreased from 68.1% to 50.7% after 1 year of treatment.
Conclusion
The Ate/Bev long-term treatment group had a lower intrahepatic tumor burden, less portal vein tumor thrombosis, and better performance status and liver function at baseline. Atezolizumab-related immunological adverse events emerged relatively early in treatment compared to the bevacizumab-related. Additionally, some patients demonstrated liver function deterioration during long-term Ate/Bev treatment.
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Head and Neck cancer
Analysis of Response and Progression Patterns of Tyrosine Kinase Inhibitors in Recurrent or Metastatic Adenoid Cystic Carcinoma: A Post Hoc Analysis of Two KCSG Phase II Trials
Youjin Kim, Bhumsuk Keam, Eun Joo Kang, Jin-Soo Kim, Hye Ryun Kim, Keun-Wook Lee, Jung Hye Kwon, Kyoung Eun Lee, Yaewon Yang, Yoon Hee Choi, Min Kyoung Kim, Jun Ho Ji, Tak Yun, Moon Young Choi, Ki Hyeong Lee, Sung-Bae Kim, Myung-Ju Ahn
Cancer Res Treat. 2024;56(4):1068-1076.   Published online April 15, 2024
DOI: https://doi.org/10.4143/crt.2024.008
AbstractAbstract PDFSupplementary MaterialPubReaderePub
Purpose
In this study, we evaluated 66 patients diagnosed with adenoid cystic carcinoma (ACC) enrolled in two Korean Cancer Study Group trials to investigate the response and progression patterns in recurrent and/or metastatic ACC treated with vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs).
Materials and Methods
We evaluated 66 patients diagnosed with ACC who were enrolled in the Korean Cancer Study Group trials. The tumor measurements, clinical data, treatment outcomes, and progression patterns of therapy were analyzed.
Results
In the 66 patients (53 receiving axitinib and 13 receiving nintedanib), the disease control rate was 61%, and three patients achieved partial response. The median follow-up, median progression-free survival (PFS), overall survival, and 6-month PFS rate were 27.6%, 12.4%, and 18.1% months and 62.1%, respectively. Among 42 patients who experienced progression, 27 (64.3%) showed target lesion progression. Bone metastasis was an independent poor prognostic factor.
Conclusion
Overall, most patients demonstrated stable disease with prolonged PFS; however, prominent target lesion progression occurred in some patients. Thus, PFS may capture VEGFR-TKI efficacy better than the objective response rate.
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Breast cancer
Clinical Significance of Major Angiogenesis-Related Effectors in Patients with Metastatic Breast Cancer Treated with Trastuzumab-Based Regimens
Helen P. Kourea, Foteinos-Ioannis Dimitrakopoulos, Georgia-Angeliki Koliou, Anna Batistatou, Kyriaki Papadopoulou, Mattheos Bobos, Anthoula Asimaki-Vlachopoulou, Sofia Chrisafi, Kitty Pavlakis, Kyriakos Chatzopoulos, Eleni Galani, George Pentheroudakis, Dimitrios Pectasides, Dimitrios Bafaloukos, Eleni Res, Pavlos Papakostas, Angelos Koutras, Vassiliki Kotoula, George Fountzilas
Cancer Res Treat. 2022;54(4):1053-1064.   Published online November 17, 2021
DOI: https://doi.org/10.4143/crt.2021.748
AbstractAbstract PDFSupplementary MaterialPubReaderePub
Purpose
Angiogenesis is a crucial phenomenon in the development and progression of breast cancer (BC), but the clinical significance of angiogenesis-related proteins in metastatic BC remains unknown. This study investigates the prognostic value of vascular endothelial growth factor receptors 1, 2, 3 (VEGFR1, VEGFR2, VEGFR3) as well as vascular endothelial growth factors A and C (VEGFA and VEGFC) in metastatic BC patients treated with trastuzumab-based regimens.
Materials and Methods
Two hundred female patients were included. Protein and mRNA expression of the studied angiogenesis-related factors were evaluated by immunohistochemistry and quantitative polymerase chain reaction, respectively.
Results
High expression of VEGFA, VEGFC, VEGFR1, VEGFR2, and VEGFR3 in the tumor cells was observed in 43.5%, 24.2%, 36%, 29.5%, and 43%, respectively. Stromal elements expressed high levels of VEGFA, VEGFC, VEGFR1, VEGFR2, and VEGFR3 in 78.9%, 93.3%, 90.7%, 90.2%, and 74.8% of tumors with available data. High tumor cell expression of VEGFR1 was a favorable prognosticator for survival among patients with human epidermal growth factor receptor 2 (HER2)–positive tumors (hazard ratio [HR], 0.55; p=0.013). A trend towards longer progression-free survival was detected univariately for patients with HER2-negative tumors and high expression of VEGFR2 (HR, 0.60; p=0.059).
Conclusion
VEGFR1 and VEGFR2 seem to have significant prognostic value in BC patients with metastatic disease treated with trastuzumab-based regimens.

Citations

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  • Apatinib beyond first progression is associated with prolonged overall survival in patients with advanced breast cancer: Results from an observational study
    Jing Wang, Jinghao Jia, Jingjing Liu, Xuemin Yao, Zhiyong Yuan
    Experimental and Therapeutic Medicine.2024;[Epub]     CrossRef
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Review Article
Anti-angiogenic Therapy in Patients with Advanced Gastric and Gastroesophageal Junction Cancer: A Systematic Review
Li-Tzong Chen, Do-Youn Oh, Min-Hee Ryu, Kun-Huei Yeh, Winnie Yeo, Roberto Carlesi, Rebecca Cheng, Jongseok Kim, Mauro Orlando, Yoon-Koo Kang
Cancer Res Treat. 2017;49(4):851-868.   Published online January 3, 2017
DOI: https://doi.org/10.4143/crt.2016.176
AbstractAbstract PDFSupplementary MaterialPubReaderePub
Despite advancements in therapy for advanced gastric and gastroesophageal junction cancers, their prognosis remains dismal. Tumor angiogenesis plays a key role in cancer growth and metastasis, and recent studies indicate that pharmacologic blockade of angiogenesis is a promising approach to therapy. In this systematic review, we summarize current literature on the clinical benefit of anti-angiogenic agents in advanced gastric cancer. We conducted a systematic search of PubMed and conference proceedings including the American Society of Clinical Oncology, the European Society for Medical Oncology, and the European Cancer Congress. Included studies aimed to prospectively evaluate the efficacy and safety of anti-angiogenic agents in advanced gastric or gastroesophageal junction cancer. Each trial investigated at least one of the following endpoints: overall survival, progression-free survival/time to progression, and/or objective response rate. Our search yielded 139 publications. Forty-two met the predefined inclusion criteria. Included studies reported outcomes with apatinib, axitinib, bevacizumab, orantinib, pazopanib, ramucirumab, regorafenib, sorafenib, sunitinib, telatinib, and vandetanib. Second-line therapy with ramucirumab and third-line therapy with apatinib are the only anti-angiogenic agents so far shown to significantly improve survival of patients with advanced gastric cancer. Overall, agents that specifically target the vascular endothelial growth factor ligand or receptor have better safety profile compared to multi-target tyrosine kinase inhibitors.

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Original Articles
Dose KRAS Mutation Status Affect on the Effect of VEGF Therapy in Metastatic Colon Cancer Patients?
Seung Tae Kim, Kyong Hwa Park, Sang Won Shin, Yeul Hong Kim
Cancer Res Treat. 2014;46(1):48-54.   Published online January 15, 2014
DOI: https://doi.org/10.4143/crt.2014.46.1.48
AbstractAbstract PDFPubReaderePub
PURPOSE
Mutations affecting the KRAS gene are an established negative predictor for anti-epidermal growth factor receptor (anti-EGFR) therapies in metastatic colorectal cancer (CRC). However, the role of KRAS mutation as a biomarker for anti-vascular endothelial growth factor (VEGF) remains controversial.
MATERIALS AND METHODS
We analyzed retrospective data from 32 CRC patients who were available for KRAS mutation status and received cytotoxic chemotherapy plus bevacizumab as a first-line therapy. Six of 32 patients received anti-EGFR therapies. We used KRAS mutation status as a predictive or prognostic factor in CRC patients receiving bevacizumab.
RESULTS
We observed mutations in KRAS in 59.4% of patients. Bevacizumab was used in combination with oxaliplatin based regimens. There was no significant difference for progression free survival (PFS) and overall survival (OS) in patients with oxaliplatin based cytotoxic chemotherapy plus bevacizumab according to the status of KRAS mutation. After first-line therapy, 28 patients (87.5%) received second-line therapy. In univariate analysis, KRAS mutations did not have a major prognostic value for PFS (hazard ratio, 1.007; 95% confidence interval [CI], 0.469 to 2.162; p>0.05) or OS (hazard ratio, 0.548; 95% CI, 0.226 to 1.328; p>0.05). In addition, anti-EGFR therapies did not affect the impact on OS.
CONCLUSION
KRAS mutation is neither a predictive for bevacizumab nor a prognostic for OS in CRC patients receiving anti-VEGF therapy.

Citations

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  • 12 Web of Science
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Clinical Implications of VEGF, TGF-beta1, and IL-1beta in Patients with Advanced Non-small Cell Lung Cancer
Ji-Won Kim, Youngil Koh, Dong-Wan Kim, Yong-Oon Ahn, Tae Min Kim, Sae-Won Han, Do-Youn Oh, Se-Hoon Lee, Seock-Ah Im, Tae-You Kim, Dae Seog Heo, Yung-Jue Bang
Cancer Res Treat. 2013;45(4):325-333.   Published online December 31, 2013
DOI: https://doi.org/10.4143/crt.2013.45.4.325
AbstractAbstract PDFPubReaderePub
PURPOSE
Vascular endothelial growth factor (VEGF)-A, VEGF165b, interleukin (IL)-1beta, and transforming growth factor (TGF)-beta1 are known to influence tumor angiogenesis. Clinical implications of these cytokines need to be elucidated.
MATERIALS AND METHODS
Using clinical data and baseline serum samples of 140 consecutive patients with advanced non-small cell lung cancer who received platinum-based combination chemotherapy, we investigated the association among serum cytokine levels, treatment outcomes, as well as leukocyte and platelet counts.
RESULTS
The median age of patients was 64 years (range, 26 to 86 years). The male to female ratio was 104:36. High TGF-beta1 and IL-1beta levels were associated with shorter progression-free survival, and high VEGF-A and IL-1beta levels were associated with shorter overall survival in the univariate analysis. VEGF165b was not related to the treatment outcomes. Leukocytosis and thrombocytosis were associated with shorter overall survival. The multivariate analysis demonstrated that VEGF-A, IL-1beta, and leukocytosis were significant prognostic factors (p=0.0497, p=0.047, and p<0.001, respectively). Leukocytosis was not associated with recent pneumonia (p=0.937) and correlated with VEGF-A (p<0.001) and TGF-beta1 (p=0.020) levels.
CONCLUSION
Serum VEGF-A, TGF-1beta, and IL-1beta levels, in addition to leukocyte and platelet counts, are shown to be associated with clinical outcomes. Leukocyte and platelet counts are correlated with serum VEGF-A and TGF-beta1 levels.

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Clinical Significance of Vascular Endothelial Growth Factors (VEGF)-C and -D in Resected Non-Small Cell Lung Cancer
Yoon Ho Ko, Chan-Kwon Jung, Myung-Ah Lee, Jae Ho Byun, Jin Hyoung Kang, Kyo Young Lee, Keon Hyun Jo, Young Pil Wang, Young Seon Hong
Cancer Res Treat. 2008;40(3):133-140.   Published online September 30, 2008
DOI: https://doi.org/10.4143/crt.2008.40.3.133
AbstractAbstract PDFPubReaderePub
Purpose

Lymphatic spread of tumor is an important prognostic factor for patients with non-small cell lung carcinoma (NSCLC). Vascular endothelial growth factor-C (VEGF-C) and VEGF-D play important roles in lymphangiogenesis via the VEGF receptor 3 (VEGFR-3). We sought to determine whether VEGF-C, VEGF-D and VEGFR-3 are involved in the clinical outcomes of patients with resected NSCLC.

Materials and Methods

Using immunohistochemical staining, we investigated the protein expressions of VEGF-C, VEGF-D and VEGFR-3 in the tissue array specimens from patients who underwent resection for NSCLC. The immunoreactivity for p53 was also examined. The clinicopathological implications of these molecules were statistically analyzed.

Results

Analysis of a total of 118 specimens showed that VEGF-C, VEGF-D and their co-expression were significantly associated with more advanced regional lymph node metastasis (p=0.019, p=0.044 and p=0.026, respectively, N2 versus N0 and N1). A VEGFR-3 expression had a strong correlation with peritumoral lymphatic invasion (p=0.047). On the multivariate analysis for survival and recurrence, pathologic N2 lymph node metastasis was the only independent prognostic factor, but none of the investigated molecules showed any statistical correlation with recurrence and survival.

Conclusions

The present study revealed that high expressions of VEGF-C and VEGF-D were strongly associated with more advanced regional lymph node metastasis in patients with resected NSCLC.

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Thymidylate Synthase, Thymidine Phosphorylase, VEGF and p53 Protein Expression in Primary Colorectal Cancer for Predicting Response to 5-fluorouracil-based Chemotherapy
Myung-Ju Ahn, Jung-Hye Choi, Ho-Suk Oh, Young-Yeul Lee, In-Soon Kim, Il-Young Choi, Kang-Hong Lee, Kang-Won Song, Chan-Kum Park
Cancer Res Treat. 2005;37(4):216-222.   Published online August 31, 2005
DOI: https://doi.org/10.4143/crt.2005.37.4.216
AbstractAbstract PDFPubReaderePub
Purpose

In the treatment of advanced metastatic colorectal cancer, several new agents, such as irinotecan and oxaliplatin, have been developed, which have improved both disease free and overall survivals. Among these agents, 5-fluorouracil (5-FU) still remains one of the most active agents, and the selection of patients who can benefit from 5-FU-based chemotherapy is still important, as those unlikely to benefit could be spared the harmful side effects. The expression levels of thymidylate synthase (TS), thymidine phosphorylase (TP) and p53 have been known to be associated with the clinical response to 5-FU-based therapy as well as the prognosis, and that of vascular endothelial growth factor (VEGF) is associated with poor survival.

Materials and Methods

The relationship between the expressions of TS, TP, VEGF and p53 in primary tumors, using immunohistochemistry, and the response of 45 metastatic colorectal cancer patients (M:F=25:20, median age 59 yrs) to 5-FU-based chemotherapy were evaluated.

Results

Thirty-seven patients were treated with 5-FU/LV/irinotecan (FOLFIRI) and 8 with 5-FU/LV/oxaplatin (FOLFOX). The overall response rate was 28.9% (13/45). When immunohistochemically analyzed with monoclonal antibodies against TS, TP, VEGF and p53, 55.6% of the patients (25/45) were positive for TS, 48.9% (22/45) for TP, 82.2% (37/45) for VEGF, and 80% (36/45) for p53. There was a significant difference in the intensity of TS expression between the clinical responders and non-responders (p=0.036). In terms of the staining pattern of TS expression, diffuse staining was correlated with a poor response (p=0.012) and poor survival (p=0.045). However, there was no correlation between the expressions of TP, VEGF or P53 and the response to chemotherapy.

Conclusion

These results suggest that the expression of TS in primary colorectal cancer might be an important prognostic factor for chemotherapy response and survival, and might be a useful therapeutic marker for the response of chemotherapy.

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Expression of c-kit and p53 in Non-small Cell Lung Cancers
Jinyoung Yoo, Chi Hong Kim, So Hyang Song, Byoung Yong Shim, Youn Ju Jeong, Meyung Im Ahn, Sung Whan Kim, Deog Gon Cho, Min Seop Jo, Kyu Do Cho, Hong Joo Cho, Hoon-Kyo Kim
Cancer Res Treat. 2004;36(3):167-172.   Published online June 30, 2004
DOI: https://doi.org/10.4143/crt.2004.36.3.167
AbstractAbstract PDFPubReaderePub
Purpose

Increasing experimental evidence indicates that abnormal expression of c-kit may be implicated in the pathogenesis of a variety of solid tumors. It has been reported that over 70% of small cell lung cancer (SCLC) contain the c-kit receptor. In the present study, a c-kit analysis has been extended to non-small cell lung cancer (NSCLC). The expressions of p53, vascular endothelial growth factor (VEGF) and cd34, in addition to c-kit, were evaluated to investigate the correlations between these proteins and to determine their potential relationships with the clinicopathological data.

Materials and Methods

Paraffin-embedded tumor sections, obtained from 147 patients with NSCLC, were immunohistochemically investigated using anti-c-kit, anti-p53, anti-VEGF and anti-cd34 antibodies.

Results

c-kit was expressed in 40 (27%) of the tumors examined: 27% of the adenocarcinomas, 27% of the squamous cell carcinomas and 29% of the undifferentiated carcinomas. p53 and VEG F immunoreactivities were present in 107 (73%) and 110 (75%) carcinomas, respectively. Anti-cd34 was negative in all samples. No associations were established among these proteins. The c-kit, however, showed a strong correlation with the T factor: T1 (n=11), 0%; T2 (n=49), 16% and T3 (n=87), 37% (p=.006).

Conclusion

It is suggested that in NSCLC c-kit is expressed relatively frequently and may become a therapeutic target for the patients with inoperable or recurrent c-kit positive tumors. The alterations in p53 probably constitute an early event, whereas the activated c-kit may contribute to tumor progression.

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Relationship between PTEN and Vascular Endothelial Growth Factor Expression in Non-Small Cell Lung Cancer
Mee Sook Roh, Jae Ik Lee, Doo Kyung Yang, Soo Keol Lee, Hyuk Chan Kwon, Mi Kyoung Park, Ki Baek Hwang, Jin A Jung
Cancer Res Treat. 2003;35(5):445-450.   Published online October 31, 2003
DOI: https://doi.org/10.4143/crt.2003.35.5.445
AbstractAbstract PDF
PURPOSE
This study was performed to determine the relationship between PTEN and vascular endothelial growth factor (VEGF) expression and to assess their roles in the tumor-induced angiogenesis and tumor progression in non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: Formalin-fixed, paraffin-embedded tissues, from 96 patients diagnosed with NSCLC, were evaluated for VEGF and PTEN expression using immunohistochemical methods. The results of the expression pattern of VEGF alone, or in combination with PTEN expression, were compared with clinicopathological parameters. RESULTS: VEGF expression was seen in 54 (56.3%) of the 96 NSCLCs evaluated, and was significantly correlated with histological type, and seen more frequently in adenocarcinomas compared to the other histological types (p<0.05). There were no significant associations between VEGF expression and tumor size, lymph node metastasis and stage. The microvessel density (MVD) determined by CD34 staining were significantly higher in tumors with VEGF expression (62.9+/-21.8) than those without (55.1+/-15.1). Loss of PTEN expression was seen in 33 (34.4%) of the 96 NSCLCs evaluated. VEGF expression was more frequently detected in the tumors with loss of PTEN expression (69.7%) than in those with PTEN expression (49.2%). When the combined VEGF/ PTEN phenotypes were divide into two groups; group I (VEGF-/PTEN+) and group II (VEGF-/ PTEN-, VEGF+/PTEN+, VEGF+/PTEN-), a significant correlation was also seen between the groups and the histologic types. There was a trend for the tumors in group II to show more frequent lymph node metastasis (50.0%) than those in group I (31.5%), although there was no statistical significance. The MVDs were significantly higher in group II (63.1+/-20.7) than in group I (53.4+/-17.2). CONCLUSION: These findings demonstrate an inverse correlation between the expressions of PTEN and VEGF. It is possible that PTEN may repress VEGF expression, and modulate VEGF-mediated angiogenesis, which suggests further analysis of the complex phenomenon of neo-angiogenesis in NSCLC is essential.

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  • Molecular and biological characterization of hepatitis B virus subgenotype F1b clusters: Unraveling its role in hepatocarcinogenesis
    María Mercedes Elizalde, Laura Mojsiejczuk, Micaela Speroni, Belén Bouzas, Luciana Tadey, Lilia Mammana, Rodolfo Héctor Campos, Diego Martín Flichman
    Frontiers in Microbiology.2022;[Epub]     CrossRef
  • KRAS mutant lung cancer cells are differentially responsive to MEK inhibitor due to AKT or STAT3 activation: Implication for combinatorial approach
    Young‐Kwang Yoon, Hwang‐Phill Kim, Sae‐Won Han, Do Youn Oh, Seock‐Ah Im, Yung‐Jue Bang, Tae‐You Kim
    Molecular Carcinogenesis.2010; 49(4): 353.     CrossRef
  • Phosphatase and Tensin Homolog Reconstruction and Vascular Endothelial Growth Factor Knockdown Synergistically Inhibit the Growth of Glioblastoma
    Hongbo Chen, Xiaomeng Shen, Caiping Guo, Huijun Zhu, Lanzhen Zhou, Yongqiang Zhu, Huixia Wang, Yi Zheng, Laiqiang Huang
    Cancer Biotherapy and Radiopharmaceuticals.2010; 25(6): 713.     CrossRef
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Clinical Implications of VEGF and p53 Expression in Squamous Cell Carcinoma of the Cervix Treated with Radiation Therapy
Jin Oh Kang, Seong Eon Hong, Dong Wook Kang
Cancer Res Treat. 2003;35(5):440-444.   Published online October 31, 2003
DOI: https://doi.org/10.4143/crt.2003.35.5.440
AbstractAbstract PDF
PURPOSE
The present study was designed to analyze the relationship between vascular endothelial growth factor (VEGF) and p53, and their impact on clinical outcome in squamous cell carcinoma of the cervix treated with radiation therapy. MATERIALS AND METHODS: This immunohistochemical study involved 23 patients with available paraffin blocks among 46 patients who were treated during the period from 1994 to 1997 in Eulji University Hospital in Korea. Anti-VEGF mouse monoclonal antibody and DO-7 anti- p53 mouse monoclonal antibody were used as the primary antibodies. Antibody binding was detected with a LSAB kit. Staining was defined as positive for VEGF and p53, when more than 10% and 5% of the tumor cells were stained out of 500 cells counted, respectively. RESULTS: FIGO stage (p=0.05) and tumor size (p=0.04) were significant prognostic factors for survival. p53 expression was present in 17 (77%) cases. There was no significant relationship between p53 staining and the clinicopathologic factors, such as FIGO stage (p=0.98), tumor size (p=0.43), lymph node status (p=0.82), parametrial invasion (p=0.96), and age (p=0.18). The five year survival rates according to the p53 expression status were 80% for the p53 negative group and 66% for the p53 positive group (p=0.58). Positive VEGF expression was observed in 11 (47%) of the total of 23 patients. Statistical evaluation of VEGF expression according to stage (p=0.36), tumor size(p=0.11), lymph node status (p=0.82), parametrial invasion (p=0.49), and age (p=0.55) revealed no significant difference in any of these parameters. The five year survival rates according to the VEGF expression status were 89% for the VEGF negative group and 41% for the VEGF positive group (p=0.07). CONCLUSION: We suggest that VEGF expression may have an effect on the prognosis of cervix cancer patients treated with radiation therapy, and further evaluation with a large sample size is warranted.

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  • Research advances in signaling pathways related to the malignant progression of HSIL to invasive cervical cancer: A review
    Huifang Wang, Chang Liu, Keer Jin, Xiang Li, Jiaxin Zheng, Danbo Wang
    Biomedicine & Pharmacotherapy.2024; 180: 117483.     CrossRef
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Prognostic Effect of Vascular Endothelial Growth Factor and Angiogenesis in Gastric Carcinoma
Myoung Im Kim, Si Young Kim, Jae Jin Lee, Hwi Joong Yoon, Yoon Wha Kim, Kyung Sam Cho
Cancer Res Treat. 2003;35(3):218-223.   Published online June 30, 2003
DOI: https://doi.org/10.4143/crt.2003.35.3.218
AbstractAbstract PDF
PURPOSE
Many studies have shown that angiogenesis has an important role in the growth, progression, and metastasis of solid tumors. Recently, several angiogenic factors have been identified. Vascular endothelial growth factor (VEGF) is a well characterized inducer of angiogenesis. In this study, we investigated the prognostic significance of the expression of VEGF in patients with an advanced gastric carcinoma. MATERIALS AND METHODS: Specimens from 54 gastric adenocarcinoma patients were stained using a polyclonal antibody against VEGF. Correlations of the expression of VEGF, microvessel density, and various other clinicopathological factors were analysed. RESULTS: Seventeen (31.5%) and 37 cases (68.5%) were VEGF-negative and positive, respectively. There was significant correlation between the expression of VEGF and pathological differentiation. There were no significant correlations between the expression of VEGF, stage and recurrence of a gastric carcinoma. The microvessel density was significantly higher in the VEGF-positive than the VEGF-negative tumors. Survivals of the VEGF-negative patients were significantly prolonged compared to those of the VEGF-positive patients. CONCLUSION: The results of this study show that the expression of VEGF may be a useful prognostic factor for patients with a gastric adenocarcinoma.

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  • RETRACTED ARTICLE: KRAS activation in gastric cancer stem-like cells promotes tumor angiogenesis and metastasis
    Changhwan Yoon, Jun Lu, Yukyung Jun, Yun-Suhk Suh, Bang-Jin Kim, Jacob E. Till, Jong Hyun Kim, Sara H. Keshavjee, Sandra Ryeom, Sam S. Yoon
    BMC Cancer.2023;[Epub]     CrossRef
  • Vascular Endothelial Growth Factor Gene Polymorphisms Associated with Prognosis for Patients with Colorectal Cancer
    Jong Gwang Kim, Yee Soo Chae, Sang Kyun Sohn, Yoon Young Cho, Joon Ho Moon, Jae Yong Park, Seoung Woo Jeon, In Taek Lee, Gyu Seog Choi, Soo-Han Jun
    Clinical Cancer Research.2008; 14(1): 62.     CrossRef
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Correlation of Mast Cell Densities, Angiogenesis and Vascular Endothelial Growth Factor in Proper Muscle Gastric Carcinomas
Eun Sook Nam, Duck Hwan Kim, Gi Taek Jang, Hae Rim Park, Jeong Rye Kim, Hyung Sik Shin
Cancer Res Treat. 2002;34(1):41-45.   Published online February 28, 2002
DOI: https://doi.org/10.4143/crt.2002.34.1.41
AbstractAbstract PDF
PURPOSE
There are increasing evidences that angiogenesis enhances tumor growth and biological aggressiveness in gastric carcinoma. Mast cells have been implicated in the angiogenic process, by secreting angiogenic factors including vascular endothelial growth factor (VEGF), or enzymes that degrade extracellular matrices. However, the exact nature of mast cells in relation to cancer is contradictory so we conducted retrospective studies, to find the significance of mast cell densities, and microvessel counts in each clinicopathologic factors, including VEGF expression, in proper muscle (PM) gastric carcinoma.
MATERIALS AND METHODS
52 specimens, obtained from patients with PM gastric carcinoma, were studied using the immunohistochemical methods, monoclonal antibodies for mast cell tryptase, factor VIII-related antigen and VEGF.
RESULTS
Mast cell densities were significantly increased in diffuse histologic type (p=0.042), infiltrating margins (p<0.0001) and VEGF positive (p=0.010) tumors.Microvessel counts were significantly higher in patients over 55 years old (p=0.024), with tumor sizes larger than >3 cm (p=0.015), diffuse histologic type (p=0.038) and lymph node metastasis (p=0.001). Similarly there were significantly increased densities in VEGF positive tumors (p<0.0001). Pearson's correlation analysis revealed a significant relationship between mast cell densities and microvessel counts (r=0.614, p<0.01), indicating a high vascular grade with increased number of mast cells.
CONCLUSION
We demonstrated a close relationship between mast cell densities, microvessel counts and VEGF expression. These results suggest that mast cells and VEGF are important regulators of tumor angiogenesis and cooperatively induce the formation of vascular stroma in PM gastric carcinomas.

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  • Mast Cells Density Positive to Tryptase Correlate with Microvascular Density in both Primary Gastric Cancer Tissue and Loco-Regional Lymph Node Metastases from Patients That Have Undergone Radical Surgery
    Michele Ammendola, Rosario Sacco, Valeria Zuccalà, Maria Luposella, Rosa Patruno, Pietro Gadaleta, Nicola Zizzo, Cosmo Gadaleta, Giovambattista De Sarro, Giuseppe Sammarco, Mihai Oltean, Girolamo Ranieri
    International Journal of Molecular Sciences.2016; 17(11): 1905.     CrossRef
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The Role of Expression of Vascular Endothelial Growth Factor (VEGF)-A and VEGF-C in Early Gastric Cancer
Jeong Hwan Yook, Shoji Natsugoe, Xiangming Che, Sumiya Ishigami, Shuichi Hokita, Masamichi Baba, Sonshin Takao, Aikou Takashi
J Korean Cancer Assoc. 2001;33(2):93-98.
AbstractAbstract PDF
PURPOSE
Tumor spread is mainly dependent on both hematogenous and lymphogeneous systems, and recently, several angiogenic factors have been identified. In the present study, we investigated whether the expressions of VEGF-A and -C are related with angiogenesis and lymph node metastasis in early gastric cancer. MATERIALS AND METHODS: A total of 97 specimens btained from patients with early gastric cancer were studied by immunohistochemical methods using anti- VEGF-A and -C polyclonal antibodies, anti-Factor VIII- related antigen antibody, and anti-p53 antibody.
RESULTS
The percentage of the positive expressions of VEGF-A and -C were 24.7% (24/97) and 25.7% (25/97), respectively. Significant differences were found between the expression of VEGF-A and lymphatic invasion and lymph node metastasis, and between expression of VEGF-C and gross type, lymphatic invasion, and lymph node metastasis (p<0.05). The mean microvessel counts in VEGF-A and -C positive tumors were significantly higher than those in VEGF-A and -C negative tumors (p<0.05). In multivariate analysis, tumor size, lymphatic invasion and VEGF-C were identified as independent factors related to lymph node metastasis (p<0.05).
CONCLUSION
The expressions of VEGF-A and -C were found to be related to angiogenic activity and VEGF-C expression correlated significantly with lymph node metastasis. The determination of VEGF-C expression may be helpful for predicting lymph node metastases in early gastric cancer, and further studies involving many specimens are warranted.
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Vascular Endothelial Growth Factor and basic Fibroblast Growth Factor Expression in Early Gastric Carcinomas: Correlation with Clinicopathologic Factors
Young Sik Kim, Hyun Deuk Cho, Seong Hwan Park, Dae Won Kim, Dae Su Kim, Jong Sang Choi, Hwa Eun Oh
J Korean Cancer Assoc. 2000;32(6):986-996.
AbstractAbstract PDF
PURPOSE
Recent studies have demonstrated that angiogenesis and its inducers such as vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) play an important role in growth, progression, and metastasis in gastric carcinomas. In this study, the authors investigated the prognostic significance of angiogenesis, VEGF, bFGF with respect to conventional clinicopathologic factors in early gastric adenocarcinomas.
MATERIALS AND METHODS
Sixty-six specimens resected from patients with early gastric carcinomas were investigated by immunohistochemical staining with antibodies against VEGF, bFGF, and CD31.
RESULTS
In this study, high expression rates of VEGF and bFGF as well as high level of angiogenesis were observed. In addition, the expression rate of VEGF was correlated well with angiogenesis. However, the clinicopathologic factors, such as age, sex, location, growth pattern, lymph node metastasis, submucosal invasion, and degree of differentiation, were not significantly associated with the expression of VEGF and bFGF, and angiogenesis.
CONCLUSION
These results suggest that controlling angiogenesis and its inducers might be a therapeutic target rather than a prognostic factor in early gastric carcinomas.
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Antiangiogenesis Gene Therapy Using Adenovirus-mediated Antisense-VEGF in Glioblastoma Multiforme
Seock Ah Im, Jeong Soo Kim, Eunmi Nam, Soon Nam Lee
J Korean Cancer Assoc. 2000;32(4):764-774.
AbstractAbstract PDF
PURPOSE
Vascular endothelial growth factor (VEGF) is a major positive effector of angiogenesis. We investigated the mechanism of tumor growth inhibition by adenoviral transfer of antisense- VEGF in glioma and the role of VEGF for in vivo growth of human glioma cells according to the stage of the tumor growth.
MATERIALS AND METHODS
Replication-deficient adenoviral vector containing the VEGF cDNA in an antisense orientation (Ad5CMV-alphaVEGF) were constructed to increase the in vivo applicability of antisense sequence. The effect of Ad5CMV-alphaVEGF was studied in vitro and in vivo with human glioma cell line U-87 MG. Immunohistochemical staining of the subcutaneous tumor with anti-VEGF antibody and CD34 antibody were performed to compare VEGF protein expression and the microvessel count respectively.
RESULTS
The growth curve of U-87 MG cells treated with Ad5CMV-alphaVEGF remained as same as that of mock-infected and Ad5(dl312)-infected U-87 MG cells in vitro, suggesting that Ad5CMV-alphaVEGF does not have direct cytotoxic effect. The growth of subcutaneous human glioma xenografts was inhibited by early intratumoral injection of Ad5CMV-alphaVEGF. Immuno histochemical staining of tumors showed that VEGF protein expression and mean microvessel counts were decreased in early Ad5CMV-alphaVEGF treatment group.
CONCLUSION
The efficient down-regulation of VEGF produced by tumor cells using Ad5CMV- alphaVEGF in early stage of glioma growth has an antitumor effect in vivo through antiangiogenic mechanism.
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Production of Soluble VEGF Receptor Mutants for Inhibition of Angiogenesis
Soo Young Yun, Yong Kil Hong, Yoon Lee, Kwangsei Kim, Hoon Kyo Kim, Young Ae Joe
J Korean Cancer Assoc. 2000;32(3):595-604.
AbstractAbstract PDF
PURPOSE
Vascular endothelial growth factor (VEGF) is a potent angiogenic factor of many solid tumors, promoting vascularization and formation of metastases. In an attempt to generate effective VEGF inhibitors, the authors constructed the VEGF receptor mutants, expressed in E. coli and Sf9 insect cells, and examined their binding to VEGF.
MATERIALS AND METHODS
The cDNA fragment encoding FLT-1 extracellular domain was cloned from human umbilical vein endothelial (HUVE) cell total RNA using RT-PCR. PCR- subcloning was performed using this template, in order to generate the deletion mutants by introducing FLT-1 partial sequences into E.coli expression vector pET-21d and baculovirus transfer vactors, pBAC-1 and pBAC-3. Two mutant proteins from baculovirus-infected insect cells were purified by heparin sepharose chromatography and immobilized into nitrdegrees Cellulose membrane followed by 125I-VEGF binding assay.
RESULTS
Two mutant receptors, sFLT (1~7) and sFLT (2~4) expressed in E.coli appeared in inclusion body as insoluble proteins. The soluble mutant receptors were produced in low yield by baculovirus/insect cell expression system. Both immobilized mutant receptors, sFLT (1~7) and sFLT (2~4) were able to bind VEGF.
CONCLUSION
These results suggest that a small soluble mutant receptor, sFLT (2~4), as well as sFLT (1~7) may be used effectively for bldegrees Cking angiogenic function of VEGF.
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Relationship between Disease Progression and Angiogenic Cytokine Vascular Endothelial Growth Factor in Patients with Stomach Cancer
S H Baick, D T Lee, S G Park, J H Won, D S Hong, H S Park
J Korean Cancer Assoc. 2000;32(2):297-303.
AbstractAbstract PDF
PURPOSE
Angiogenesis is required for tumor growth and metastasi. Vascular endothelial growth factor (VEGF) is one of the most important angiogenic cytokines. VEGF was expressed by several human solid tumors and serum VEGF levels have previously been shown to be raised in patients with breast, gastrointestinal tract, renal, ovarian cancer and melanoma. Tumor-derived VEGF plays a pivotal role in malignant ascites formation likely by increasing vascular permeability. In present study, amount of VEGF in plasmas and tumor tissues and cytology-proven malignant ascites were tested and compared with their normal counterparts and tumor stage to know relationship between the disease progression and VEGF quantitation in patients with stomach cancer. Also change of plasma VEGF level after tumor resection was performed.
MATERIALS AND METHODS
VEGF level was measured by ELISA in plasmas from 81 patients and tumors and peritumoral mucosas (5 cm from the tumor) from 43 patients and malignant ascites from 14 patients with gastric carcinoma. Also level of plasma VEGF from 48 patients was measured after tumor resection.
RESULTS
VEGF levels were significantly higher in plasma and in tumor tissues than in normal controls and in peritumoral mucosas. The levels of VEGF in plasma and tumor tissue were significantly correlated with the stage of disease. Moreover Tl showed significantly elevation of plasma VEGF level than those of controls. A significant correlation was found between plasma VEGF and tumor VEGF levels in stomach cancer patients. VEGF levels in fluid of cytology- proven malignant ascites were higher than in ascitic fluid with benign diseases. Plasma VEGF level fell after tumor resection, CONCLUSION: VEGF could act in a supporting tumor progression and may be useful for predicting prognosis of patients with gastric carcinoma.
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The Prognostic Role of Vascular Endothelial Growth Factor (VEGF) Expression and Angiogenesis in Curatively Resected Non-Small Cell Lung Cancer
Soon Nam Lee
J Korean Cancer Assoc. 1999;31(6):1210-1218.
AbstractAbstract PDF
PURPOSE
Angiogenesis is an essential component of tumor growth and metastasis, and vascular endothelial growth factor (VEGF) is one of the important angiogenic factor. To evaluate the prognostic roles of angiogenesis and VEGF expression in patients with non-small cell lung cancer, the relationships between microvessel counts (MVC), VEGF expressions in tumor tissues, clinicopathologic features and overall survival were analysed.
MATERIALS AND METHODS
Thirty-seven patients with curatively resected non-small cell lung cancer were evaluated. Tumor tissues were stained by anti-CD34 and anti-VEGF monoclonal antibody using immunohistochemical method to assess MVC and VEGF expression and analysed the relationship of MVC, VEGF, and clinicopathologic findings.
RESULTS
Mean MVC of all tumor tissues was 33.89+/-24.12 and VEGF were expressed in 26 tissues (70%). There was no correlation between VEGF expression and MVC. Mean MVC was significantly higher in patients with recurrence than in those without recurrence (50.58+/-29.33 vs 19.5+/-11.7, p=0.004). There were no correlation between VEGF expression and clinicopathologic findings and overall survival. In univariate analysis, MVC (p=0.0431), lymph node involvement (p=0.0046), histologic type (squamous vs nonsquamous) (p=0.0072) were significant prognostic factors with respect to overall survival.
CONCLUSION
In patients with non-small cell lung cancer who underwent curative resectin of tumors, VEGF expression in tumor tissue was not correlated with MVC and survival. But MVC was correlated with tumor recurrence and survival, thus MVC may be used as one of prognostic factors in non-small cell lung cancer.
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Immunohistochemical Expression of CD34 and Vascular Endothelial Growth Factor in Hepatocellular Carcinoma
Yeong Ok Kim, Bang Hur
J Korean Cancer Assoc. 1999;31(4):802-810.
AbstractAbstract PDF
PURPOSE
Angiogenesis plays an important role in progression, invasion and metastasis of solid tumors. The Vascular Endothelial Growth Factor (VEGF) is thought to be a selective mitogen for endothelial cells. Hepatocellular carcinoma is a typical hypervascular tumor. However, the relationship between angiogenesis and angiogenic factor in hepatocellular carcinoma has not been evaluated. We investigated the relationship between microvessel density (MVD) and expression of VEGF in hepatocellular carcinoma.
MATERIALS AND METHODS
Immunohistochemlcal staining, using anti-CD34 and anti-VEGF antibodies, was applied in 32 cases of hepatocellular carcinoma. Also, relationship between these neovascular factors (MVD and VEGF expression) and clinicopathologic parameters such as tumor size, bistologic grade, alpha-fetoprotein level, hepatitis B virus surface antigen, presence of cirrhosis and survival was evaluated.
RESULTS
CD34 was reactive throughout the neoplastic tissue, albeit it was confined to a few periportal sinusoids and vessels in fibrous septa of adjacent cirrhotic liver. MVD was 59.6+22.7 and 44.3+21.5 in hepatocellular carcinoma and cirrhosis, respectively. VEGF was expressed in 9 cases (28.1%) of hepatocellular carcinoma, which was localized to the cytoplasm. MVD and VEGF expression was not significantly correlated (P>0.05). MVD was correlated with presence of cirrhosis and inversely conelated with alpha- fetoprotein level (p<0.05). MVD was not correlated with tumor size, presence of HBs antigen, histologic grade and survival (P>0.05). Expression of VEGF was not correlated with all clinicopathologic parameters (P>0.05).
CONCLUSION
These results indicate that MVD in hepatocellular carcinoma is not directly correlated with VEGF expression, and suggest that other angiogenic factor may be involved in neovascularization of hepatocellular carcinoma. However, CD34 expression is closely associated with neovascular process in cirrhosis and hepatocelluar carcinoma.
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