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The effects of bevacizumab on intestinal anastomotic healing in rabbits

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Abstract

Purposes

The aim of this study was to investigate the effects of the preoperative administration of BV on the healing process of intestinal anastomosis in a rabbit model.

Methods

Twenty male white rabbits were randomly divided into two groups. The control group received saline 1 week before surgery, and the BV group received intravenous BV 1 week before surgery. Each rabbit underwent an enteroenterostomy and a colocolostomy. On postoperative day 7, the bursting pressures of the anastomoses, CD31 and α-smooth muscle actin (α-SMA) staining by immunohistochemistry, the gene expression of α-SMA, and collagen deposition using Picrosirius Red at the site of anastomosis were evaluated.

Results

The bursting pressure of small bowel anastomoses was significantly lower in the BV group than in the control group (control 184 ± 10 mmHg vs. BV 140 ± 9 mmHg; p = 0.004). The microvessel counts in the anastomotic tissue were significantly lower in the BV group than in the control group in both the small bowel (p = 0.023) and colon (p = 0.008). The expression of α-SMA, and the degree of collagen deposition decreased in the anastomotic tissue in the BV group compared with the control group.

Conclusion

The preoperative use of BV may therefore negatively affect the rigidity of intestinal anastomosis.

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References

  1. Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer (J Int Cancer). 2010;127:2893–917.

    Article  CAS  Google Scholar 

  2. Van Cutsem E, Kohne CH, Hitre E, Zaluski J, Chang Chien CR, Makhson A, et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med. 2009;360:1408–17.

    Article  PubMed  Google Scholar 

  3. Douillard JY, Siena S, Cassidy J, Tabernero J, Burkes R, Barugel M, et al. Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study. J Clin Oncol. 2010;28:4697–705.

    Article  CAS  PubMed  Google Scholar 

  4. Jain RK. Normalizing tumor vasculature with anti-angiogenic therapy: a new paradigm for combination therapy. Nat Med. 2001;7:987–9.

    Article  CAS  PubMed  Google Scholar 

  5. Hofland KF, Hansen S, Sorensen M, Engelholm S, Schultz HP, Muhic A, et al. Neoadjuvant bevacizumab and irinotecan versus bevacizumab and temozolomide followed by concomitant chemoradiotherapy in newly diagnosed glioblastoma multiforme: a randomized phase II study. Acta Oncol. 2014;53:939–44.

    Article  CAS  PubMed  Google Scholar 

  6. Bear HD, Tang G, Rastogi P, Geyer CE Jr, Robidoux A, Atkins JN, et al. Bevacizumab added to neoadjuvant chemotherapy for breast cancer. N Engl J Med. 2012;366:310–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Gordon MS, Cunningham D. Managing patients treated with bevacizumab combination therapy. Oncology. 2005;69(Suppl 3):25–33.

    Article  CAS  PubMed  Google Scholar 

  8. Uehara K, Hiramatsu K, Maeda A, Sakamoto E, Inoue M, Kobayashi S, et al. Neoadjuvant oxaliplatin and capecitabine and bevacizumab without radiotherapy for poor-risk rectal cancer: N-SOG 03 Phase II trial. Jpn J Clin Oncol. 2013;43:964–71.

    Article  PubMed  Google Scholar 

  9. Ehrlich HP, Tarver H, Hunt TK. Effects of vitamin A and glucocorticoids upon inflammation and collagen synthesis. Ann Surg. 1973;177:222–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Rijcken E, Sachs L, Fuchs T, Spiegel HU, Neumann PA. Growth factors and gastrointestinal anastomotic healing. J Surg Res. 2014;187:202–10.

    Article  CAS  PubMed  Google Scholar 

  11. Hinz B, Phan SH, Thannickal VJ, Galli A, Bochaton-Piallat ML, Gabbiani G. The myofibroblast: one function, multiple origins. Am J Pathol. 2007;170:1807–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Kube R, Mroczkowski P, Granowski D, Benedix F, Sahm M, Schmidt U, et al. Anastomotic leakage after colon cancer surgery: a predictor of significant morbidity and hospital mortality, and diminished tumour-free survival. Eur J Surg Oncol. 2010;36:120–4.

    Article  CAS  PubMed  Google Scholar 

  13. August DA, Serrano D, Poplin E. “Spontaneous”, delayed colon and rectal anastomotic complications associated with bevacizumab therapy. J Surg Oncol. 2008;97:180–5.

    Article  CAS  PubMed  Google Scholar 

  14. Gruenberger B, Tamandl D, Schueller J, Scheithauer W, Zielinski C, Herbst F, et al. Bevacizumab, capecitabine, and oxaliplatin as neoadjuvant therapy for patients with potentially curable metastatic colorectal cancer. J Clin Oncol. 2008;26:1830–5.

    Article  CAS  PubMed  Google Scholar 

  15. Starlinger P, Alidzanovic L, Schauer D, Maier T, Nemeth C, Perisanidis B, et al. Neoadjuvant bevacizumab persistently inactivates VEGF at the time of surgery despite preoperative cessation. Br J Cancer. 2012;107:961–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Kuzu MA, Koksoy C, Kale T, Demirpence E, Renda N. Experimental study of the effect of preoperative 5-fluorouracil on the integrity of colonic anastomoses. Br J Surg. 1998;85:236–9.

    Article  CAS  PubMed  Google Scholar 

  17. van der Kolk BM, de Man BM, Wobbes T, Hendriks T. Is early post-operative treatment with 5-fluorouracil possible without affecting anastomotic strength in the intestine? Br J Cancer. 1999;79:545–50.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Ozel L, Ozel MS, Toros AB, Kara M, Ozkan KS, Tellioglu G, et al. Effect of early preoperative 5-fluorouracil on the integrity of colonic anastomoses in rats. World J Gastroenterol. 2009;15:4156–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Pavlidis ET, Ballas KD, Symeonidis NG, Psarras K, Koliakos G, Kouzi-Koliakos K, et al. The effect of bevacizumab on colon anastomotic healing in rats. Int J Colorectal Dis. 2010;25:1465–73.

    Article  PubMed  Google Scholar 

  20. Lin YS, Nguyen C, Mendoza JL, Escandon E, Fei D, Meng YG, et al. Preclinical pharmacokinetics, interspecies scaling, and tissue distribution of a humanized monoclonal antibody against vascular endothelial growth factor. J Pharmacol Exp Ther. 1999;288:371–8.

    CAS  PubMed  Google Scholar 

  21. Fuh G, Wu P, Liang WC, Ultsch M, Lee CV, Moffat B, et al. Structure-function studies of two synthetic anti-vascular endothelial growth factor Fabs and comparison with the Avastin Fab. J Biol Chem. 2006;281:6625–31.

    Article  CAS  PubMed  Google Scholar 

  22. Christensen H, Oxlund H. Growth hormone increases the collagen deposition rate and breaking strength of left colonic anastomoses in rats. Surgery. 1994;116:550–6.

    CAS  PubMed  Google Scholar 

  23. Christoforidis JB, Wang J, Jiang A, Willard J, Pratt C, Abdel-Rasoul M, et al. The effect of intravitreal bevacizumab and ranibizumab on cutaneous tensile strength during wound healing. Clin Ophthalmol. 2013;7:185–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Park HY, Kim JH, Park CK. VEGF induces TGF-beta1 expression and myofibroblast transformation after glaucoma surgery. Am J Pathol. 2013;182:2147–54.

    Article  CAS  PubMed  Google Scholar 

  25. Hawley PR, Faulk WP, Hunt TK, Dunphy JE. Collagenase activity in the gastro-intestinal tract. Br J Surg. 1970;57:896–900.

    Article  CAS  PubMed  Google Scholar 

  26. van der Flier M, Coenjaerts FE, Mwinzi PN, Rijkers E, Ruyken M, Scharringa J, et al. Antibody neutralization of vascular endothelial growth factor (VEGF) fails to attenuate vascular permeability and brain edema in experimental pneumococcal meningitis. J Neuroimmunol. 2005;160:170–7.

    Article  PubMed  Google Scholar 

  27. Passot G, Dupre A, Rivoire M, Mohamed F, Bakrin N, Glehen O. Intraperitoneal bevacizumab combined with cytoreductive surgery: a pre-clinical study of tolerance and pharmacokinetics in an animal model. Clin Transl Oncol. 2012;14:931–6.

    Article  CAS  PubMed  Google Scholar 

  28. Benson AB 3rd, Venook AP, Bekaii-Saab T, Chan E, Chen YJ, Cooper HS, et al. Colon cancer, version 3.2014. J Natl Compr Cancer Netw JNCCN. 2014;12:1028–59.

    CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Division of Surgical Oncology, Department of Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan

    Hayato Nakamura, Yukihiro Yokoyama, Keisuke Uehara, Toshio Kokuryo, Junpei Yamaguchi & Masato Nagino

  2. Department of Pathology, Japanese Red Cross Nagoya Daini Hospital, Nagoya, Japan

    Toyonori Tsuzuki

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  1. Hayato Nakamura
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  2. Yukihiro Yokoyama
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  5. Junpei Yamaguchi
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Corresponding author

Correspondence to Yukihiro Yokoyama.

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Conflict of interest

Chugai Pharmaceutical Co., Ltd, Tokyo, Japan provided the BV used in this study. All the authors declare that they have no conflicts of interest. The sponsor had played no role in the study design, conduct of the study, data collection, data management and interpretation, preparation of this article, or approval of the article.

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Nakamura, H., Yokoyama, Y., Uehara, K. et al. The effects of bevacizumab on intestinal anastomotic healing in rabbits. Surg Today 46, 1456–1463 (2016). https://doi.org/10.1007/s00595-016-1342-4

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  • DOI: https://doi.org/10.1007/s00595-016-1342-4

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