Clinical Research Papers:

Histopathological investigation of glioblastomas resected under bevacizumab treatment

Ryota Tamura, Toshihide Tanaka, Keisuke Miyake, Yusuke Tabei, Kentaro Ohara, Oltea Sampetrean, Maya Kono, Katsuhiro Mizutani, Yohei Yamamoto, Yuichi Murayama, Takashi Tamiya, Kazunari Yoshida and Hikaru Sasaki _

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Oncotarget. 2016; 7:52423-52435. https://doi.org/10.18632/oncotarget.9387

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Ryota Tamura1, Toshihide Tanaka2, Keisuke Miyake3, Yusuke Tabei4, Kentaro Ohara5, Oltea Sampetrean6, Maya Kono1, Katsuhiro Mizutani1, Yohei Yamamoto2, Yuichi Murayama7, Takashi Tamiya3, Kazunari Yoshida1 and Hikaru Sasaki1

1 Department of Neurosurgery, Keio University School of Medicine, Shinanomachi, Shinjuku-ku, Tokyo, Japan

2 Department of Neurosurgery, Jikei University Kashiwa Hospital, Kashiwashita, Kashiwa-shi, Chiba, Japan

3 Department of Neurosurgery, Kagawa University Hospital, Ikedo, Mituki-cho, Kita-gun, Kagawa, Japan

4 Department of Neurosurgery, Japan Red Cross Medical Center, Hiroo, Shibuya-ku, Tokyo, Japan

5 Division of Diagnostic Pathology, Keio University School of Medicine, Shinanomachi, Shinjuku-ku, Tokyo, Japan

6 Division of Gene Regulation, Institute for Advanced Medical Research, Keio University School of Medicine, Shinanomachi, Shinjuku-ku, Tokyo, Japan

7 Department of Neurosurgery, Jikei University Hospital, Nishishinbashi, Minato-ku, Tokyo, Japan

Correspondence to:

Hikaru Sasaki, email:

Keywords: bevacizumab; neoadjuvant; vascular normalization; hypoxia; glioma stem cell

Received: February 08, 2016 Accepted: May 09, 2016 Published: May 17, 2016


To date, no clinical observations have been reported for histopathological changes in human gliomas under antiangiogenic treatment.

We collected six glioblastomas resected under bevacizumab treatment. Histopathological investigation was performed by hematoxilyn-eosin staining and immunohistochemistry for CD34, VEGF, VEGFR1/2, HIF-1α, CA9, and nestin as compared to eleven control glioblastomas to assess the differences in histological features, microvessel density, expression of VEGF and its receptors, tumor oxygenation, and status of glioma stem-like cells.

In the six tumors resected under bevacizumab, microvascular proliferation was absent, and microvessel density had significantly decreased compared with that of the controls. The expressions of VEGF and its receptors were downregulated in two cases of partial response. HIF-1α or CA9 expression was decreased in five of the six tumors, whereas the decreased expression of these markers was noted in only one of the 11 control glioblastomas. The expression of nestin significantly decreased in the six tumors compared with that of the controls, with the remaining nestin-positive cells being relatively concentrated around vessels.

We provide the first clinicopathological evidence that antiangiogenic therapy induces the apparent normalization of vascular structure, decrease of microvessel density, and improvement of tumor oxygenation in glioblastomas. These in situ observations will help to optimize therapy.

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