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Published in: Clinical and Experimental Medicine 4/2017

01-11-2017 | Original Article

Spatial distribution of mast cells around vessels and glands in human gastric carcinoma

Authors: Diego Guidolin, Simona Ruggieri, Tiziana Annese, Cinzia Tortorella, Andrea Marzullo, Domenico Ribatti

Published in: Clinical and Experimental Medicine | Issue 4/2017

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Abstract

The spatial distribution of mast cells inside the tumor stroma has been little investigated. In this study, we have evaluated tumor mast cells (MCs) distribution in gastric cancer through the analysis of the morphological features of the spatial patterns generated by these cells, including size, shape, and architecture of the cell pattern. The pattern of distribution of tryptase- and chymase-positive MCs around the blood vessels and gastric glands in human gastric adenocarcinoma samples was investigated by immunohistochemical techniques and by introducing a quantitative approach to characterize the spatial distribution of MCs. In human gastric cancer, both chymase-positive MC and vessels exhibited significant deviations from randomness for what it concerns their spatial relationship with gastric parenchyma. As indicated by cell-to-gland distances shorter than expected by chance, in grade II samples a preferential localization of chymase-positive MC near the gastric glands was observed. Interestingly, the same type of spatial association was exhibited by vessels in grade IV samples, where vessel-to-gland distances shorter than expected by chance were observed. These two findings allow to speculate about a sequence of events in which a subpopulation of MC is first recruited around gastric parenchyma to drive the subsequent development of a vascular support to the tissue.
Literature
1.
go back to reference Ammendola M, Sacco R, Donato G, et al. Mast cell positivity to tryptase correlates with metastatic lymph nodes in gastrointestinal cancer patients treated surgically. Oncology. 2013;85:111–6.CrossRefPubMed Ammendola M, Sacco R, Donato G, et al. Mast cell positivity to tryptase correlates with metastatic lymph nodes in gastrointestinal cancer patients treated surgically. Oncology. 2013;85:111–6.CrossRefPubMed
2.
go back to reference Araya M, Terashima M, Takagane A, et al. Microvessel count predicts metastasis and prognosis in patients with gastric cancer. J Surg Oncol. 1997;65:232–6.CrossRefPubMed Araya M, Terashima M, Takagane A, et al. Microvessel count predicts metastasis and prognosis in patients with gastric cancer. J Surg Oncol. 1997;65:232–6.CrossRefPubMed
3.
go back to reference Maeda K, Chung YS, Takatsuka S, et al. Tumour angiogenesis and tumour cell proliferation as prognostic indicators in gastric carcinoma. Br J Cancer. 1995;72:319–23.CrossRefPubMedPubMedCentral Maeda K, Chung YS, Takatsuka S, et al. Tumour angiogenesis and tumour cell proliferation as prognostic indicators in gastric carcinoma. Br J Cancer. 1995;72:319–23.CrossRefPubMedPubMedCentral
4.
go back to reference Takahashi Y, Cleary KR, Mai M, Kitadai Y, Bucana CD, Ellis LM. Significance of vessel count and vascular endothelial growth factor and its receptor (KDR) in intestinal-type gastric cancer. Clin Cancer Res. 1996;2:1679–84.PubMed Takahashi Y, Cleary KR, Mai M, Kitadai Y, Bucana CD, Ellis LM. Significance of vessel count and vascular endothelial growth factor and its receptor (KDR) in intestinal-type gastric cancer. Clin Cancer Res. 1996;2:1679–84.PubMed
5.
go back to reference Tanigawa N, Amaya H, Matsumura M, Shimomatsuya T. Association of tumour vasculature with tumour progression and overall survival of patients with non-early gastric carcinomas. Br J Cancer. 1997;75:566–71.CrossRefPubMedPubMedCentral Tanigawa N, Amaya H, Matsumura M, Shimomatsuya T. Association of tumour vasculature with tumour progression and overall survival of patients with non-early gastric carcinomas. Br J Cancer. 1997;75:566–71.CrossRefPubMedPubMedCentral
6.
go back to reference Tanigawa N, Amaya H, Matsumura M, Shimomatsuya T. Correlation between expression of vascular endothelial growth factor and tumor vascularity, and patient outcome in human gastric carcinoma. J Clin Oncol. 1997;15:826–32.CrossRefPubMed Tanigawa N, Amaya H, Matsumura M, Shimomatsuya T. Correlation between expression of vascular endothelial growth factor and tumor vascularity, and patient outcome in human gastric carcinoma. J Clin Oncol. 1997;15:826–32.CrossRefPubMed
7.
go back to reference Tanigawa N, Amaya H, Matsumura M, et al. Extent of tumor vascularization correlates with prognosis and hematogenous metastasis in gastric carcinomas. Cancer Res. 1996;56:2671–6.PubMed Tanigawa N, Amaya H, Matsumura M, et al. Extent of tumor vascularization correlates with prognosis and hematogenous metastasis in gastric carcinomas. Cancer Res. 1996;56:2671–6.PubMed
8.
go back to reference Maeda K, Y-s Chung, Ogawa Y, et al. Prognostic value of vascular endothelial growth factor expression in gastric carcinoma. Cancer. 1996;77:858–63.CrossRefPubMed Maeda K, Y-s Chung, Ogawa Y, et al. Prognostic value of vascular endothelial growth factor expression in gastric carcinoma. Cancer. 1996;77:858–63.CrossRefPubMed
9.
go back to reference Takahashi Y, Bucana CD, Akagi Y, et al. Significance of platelet-derived endothelial cell growth factor in the angiogenesis of human gastric cancer. Clin Cancer Res. 1998;4:429–34.PubMed Takahashi Y, Bucana CD, Akagi Y, et al. Significance of platelet-derived endothelial cell growth factor in the angiogenesis of human gastric cancer. Clin Cancer Res. 1998;4:429–34.PubMed
10.
go back to reference Maehara Y, Kabashima A, Koga T, et al. Vascular invasion and potential for tumor angiogenesis and metastasis in gastric carcinoma. Surgery. 2000;128:408–16.CrossRefPubMed Maehara Y, Kabashima A, Koga T, et al. Vascular invasion and potential for tumor angiogenesis and metastasis in gastric carcinoma. Surgery. 2000;128:408–16.CrossRefPubMed
11.
go back to reference Zhang H, Wu J, Meng L, Shou CC. Expression of vascular endothelial growth factor and its receptors KDR and Flt-1 in gastric cancer cells. World J Gastroenterol. 2002;8:994–8.CrossRefPubMedPubMedCentral Zhang H, Wu J, Meng L, Shou CC. Expression of vascular endothelial growth factor and its receptors KDR and Flt-1 in gastric cancer cells. World J Gastroenterol. 2002;8:994–8.CrossRefPubMedPubMedCentral
12.
14.
go back to reference Ammendola M, Sacco R, Sammarco G, et al. Mast cells positive to tryptase and c-Kit receptor expressing cells correlates with angiogenesis in gastric cancer patients surgically treated. Gastroenterol Res Pract. 2013;2013:1–5.CrossRef Ammendola M, Sacco R, Sammarco G, et al. Mast cells positive to tryptase and c-Kit receptor expressing cells correlates with angiogenesis in gastric cancer patients surgically treated. Gastroenterol Res Pract. 2013;2013:1–5.CrossRef
15.
go back to reference Guidolin D, Zunarelli E, Genedani S, et al. Opposite patterns of age-associated changes in neurons and glial cells of the thalamus of human brain. Neurobiol Aging. 2008;29:926–36.CrossRefPubMed Guidolin D, Zunarelli E, Genedani S, et al. Opposite patterns of age-associated changes in neurons and glial cells of the thalamus of human brain. Neurobiol Aging. 2008;29:926–36.CrossRefPubMed
16.
go back to reference Ruifrok AC, Katz RL, Johnston DA. Comparison of quantification of histochemical staining by hue-saturation-intensity (HSI) transformation and color-deconvolution. Appl Immunohisto Mol Morphol. 2003;11:85–91. Ruifrok AC, Katz RL, Johnston DA. Comparison of quantification of histochemical staining by hue-saturation-intensity (HSI) transformation and color-deconvolution. Appl Immunohisto Mol Morphol. 2003;11:85–91.
17.
go back to reference Guidolin D, Marinaccio C, Tortorella C, et al. A fractal analysis of the spatial distribution of tumoral mast cells in lymph nodes and bone marrow. Exp Cell Res. 2015;339:96–102.CrossRefPubMed Guidolin D, Marinaccio C, Tortorella C, et al. A fractal analysis of the spatial distribution of tumoral mast cells in lymph nodes and bone marrow. Exp Cell Res. 2015;339:96–102.CrossRefPubMed
18.
go back to reference Russ JC. The image processing handbook, vol. 6. Boca Raton: Taylor & Francis; 2011. Russ JC. The image processing handbook, vol. 6. Boca Raton: Taylor & Francis; 2011.
19.
go back to reference Besag J, Diggle PJ. Simple Monte Carlo tests for spatial pattern. Appl Stat. 1977;26:327.CrossRef Besag J, Diggle PJ. Simple Monte Carlo tests for spatial pattern. Appl Stat. 1977;26:327.CrossRef
20.
go back to reference Gatrell AC, Bailey TC, Diggle PJ, Rowlingson BS. spatial point pattern analysis and its application in geographical epidemiology. Trans Inst Br Geogr. 1996;21:256.CrossRef Gatrell AC, Bailey TC, Diggle PJ, Rowlingson BS. spatial point pattern analysis and its application in geographical epidemiology. Trans Inst Br Geogr. 1996;21:256.CrossRef
21.
go back to reference Philimonenko AA, Janáček J, Hozák P. Statistical evaluation of colocalization patterns in immunogold labeling experiments. J Struct Biol. 2000;132:201–10.CrossRefPubMed Philimonenko AA, Janáček J, Hozák P. Statistical evaluation of colocalization patterns in immunogold labeling experiments. J Struct Biol. 2000;132:201–10.CrossRefPubMed
22.
go back to reference Trabucchi E, Radaelli E, Marazzi M, et al. The role of mast cells in wound healing. Int J Tissue React. 1988;10:367–72.PubMed Trabucchi E, Radaelli E, Marazzi M, et al. The role of mast cells in wound healing. Int J Tissue React. 1988;10:367–72.PubMed
23.
go back to reference Krishna A, Beesley K, Terranova PF. Histamine, mast cells and ovarian function. J Endocrinol. 1989;120:363–71.CrossRefPubMed Krishna A, Beesley K, Terranova PF. Histamine, mast cells and ovarian function. J Endocrinol. 1989;120:363–71.CrossRefPubMed
24.
go back to reference Yamada T, Sawatsubashi M, Itoh Y, et al. Localization of vascular endothelial growth factor in synovial membrane mast cells: examination with ”multi-labelling subtraction immunostaining”. Virchows Arch. 1998;433:567–70.CrossRefPubMed Yamada T, Sawatsubashi M, Itoh Y, et al. Localization of vascular endothelial growth factor in synovial membrane mast cells: examination with ”multi-labelling subtraction immunostaining”. Virchows Arch. 1998;433:567–70.CrossRefPubMed
25.
go back to reference Glowacki J, Mulliken JB. Mast cells in hemangiomas and vascular malformations. Pediatrics. 1982;70:48–51.PubMed Glowacki J, Mulliken JB. Mast cells in hemangiomas and vascular malformations. Pediatrics. 1982;70:48–51.PubMed
26.
go back to reference Qu Z, Kayton RJ, Ahmadi P, et al. Ultrastructural immunolocalization of basic fibroblast growth factor in mast cell secretory granules: morphological evidence for bFGF release through degranulation. J Histochem Cytochem. 1998;46:1119–28.CrossRefPubMed Qu Z, Kayton RJ, Ahmadi P, et al. Ultrastructural immunolocalization of basic fibroblast growth factor in mast cell secretory granules: morphological evidence for bFGF release through degranulation. J Histochem Cytochem. 1998;46:1119–28.CrossRefPubMed
27.
go back to reference Marinaccio C, Ingravallo G, Gaudio F, et al. Microvascular density, CD68 and tryptase expression in human diffuse large B-cell lymphoma. Leuk Res. 2014;38:1374–7.CrossRefPubMed Marinaccio C, Ingravallo G, Gaudio F, et al. Microvascular density, CD68 and tryptase expression in human diffuse large B-cell lymphoma. Leuk Res. 2014;38:1374–7.CrossRefPubMed
28.
29.
go back to reference Ribatti D, Vacca A, Marzullo A, et al. Angiogenesis and mast cell density with tryptase activity increase simultaneously with pathological progression in B-cell non-Hodgkin’s lymphomas. Int J Cancer. 2000;85:171–5.CrossRefPubMed Ribatti D, Vacca A, Marzullo A, et al. Angiogenesis and mast cell density with tryptase activity increase simultaneously with pathological progression in B-cell non-Hodgkin’s lymphomas. Int J Cancer. 2000;85:171–5.CrossRefPubMed
30.
go back to reference Ribatti D, Vacca A, Nico B, et al. Bone marrow angiogenesis and mast cell density increase simultaneously with progression of human multiple myeloma. Br J Cancer. 1999;79:451–5.CrossRefPubMedPubMedCentral Ribatti D, Vacca A, Nico B, et al. Bone marrow angiogenesis and mast cell density increase simultaneously with progression of human multiple myeloma. Br J Cancer. 1999;79:451–5.CrossRefPubMedPubMedCentral
31.
go back to reference Ribatti D, Polimeno G, Vacca A, et al. Correlation of bone marrow angiogenesis and mast cells with tryptase activity in myelodysplastic syndromes. Leukemia. 2002;16:1680–4.CrossRefPubMed Ribatti D, Polimeno G, Vacca A, et al. Correlation of bone marrow angiogenesis and mast cells with tryptase activity in myelodysplastic syndromes. Leukemia. 2002;16:1680–4.CrossRefPubMed
32.
go back to reference Molica S, Vacca A, Crivellato E, Cuneo A, Ribatti D. Tryptase-positive mast cells predict clinical outcome of patients with early B-cell chronic lymphocytic leukemia. Eur J Haematol. 2003;71:137–9.CrossRefPubMed Molica S, Vacca A, Crivellato E, Cuneo A, Ribatti D. Tryptase-positive mast cells predict clinical outcome of patients with early B-cell chronic lymphocytic leukemia. Eur J Haematol. 2003;71:137–9.CrossRefPubMed
33.
go back to reference Bowrey PF, King J, Magarey C, et al. Histamine, mast cells and tumour cell proliferation in breast cancer: does preoperative cimetidine administration have an effect? Br J Cancer. 2000;82:167–70.CrossRefPubMed Bowrey PF, King J, Magarey C, et al. Histamine, mast cells and tumour cell proliferation in breast cancer: does preoperative cimetidine administration have an effect? Br J Cancer. 2000;82:167–70.CrossRefPubMed
34.
go back to reference Hartveit F. Mast cells and metachromasia in human breast cancer: Their occurrence, significance and consequence: a preliminary report. J Pathol. 1981;134:7–11.CrossRefPubMed Hartveit F. Mast cells and metachromasia in human breast cancer: Their occurrence, significance and consequence: a preliminary report. J Pathol. 1981;134:7–11.CrossRefPubMed
35.
go back to reference Lachter J, Stein M, Lichtig C, Eidelman S, Munichor M. Mast cells in colorectal neoplasias and premalignant disorders. Dis Colon Rectum. 1995;38:290–3.CrossRefPubMed Lachter J, Stein M, Lichtig C, Eidelman S, Munichor M. Mast cells in colorectal neoplasias and premalignant disorders. Dis Colon Rectum. 1995;38:290–3.CrossRefPubMed
36.
go back to reference Benitez-Bribiesca L, Wong A, Utrera D, Castellanos E. The role of mast cell tryptase in neoangiogenesis of premalignant and malignant lesions of the uterine cervix. J Histochem Cytochem. 2001;49:1061–2.CrossRefPubMed Benitez-Bribiesca L, Wong A, Utrera D, Castellanos E. The role of mast cell tryptase in neoangiogenesis of premalignant and malignant lesions of the uterine cervix. J Histochem Cytochem. 2001;49:1061–2.CrossRefPubMed
37.
38.
go back to reference Ribatti D, Finato N, Crivellato E, et al. Neovascularization and mast cells with tryptase activity increase simultaneously with pathologic progression in human endometrial cancer. Am J Obstet Gynecol. 2005;193:1961–5.CrossRefPubMed Ribatti D, Finato N, Crivellato E, et al. Neovascularization and mast cells with tryptase activity increase simultaneously with pathologic progression in human endometrial cancer. Am J Obstet Gynecol. 2005;193:1961–5.CrossRefPubMed
39.
go back to reference Dvorak AM, Mihm MC, Osage JE, Dvorak HF. Melanoma. An ultrastructural study of the host inflammatory and vascular responses. J Invest Dermatol. 1980;75:388–93.CrossRefPubMed Dvorak AM, Mihm MC, Osage JE, Dvorak HF. Melanoma. An ultrastructural study of the host inflammatory and vascular responses. J Invest Dermatol. 1980;75:388–93.CrossRefPubMed
40.
go back to reference Reed JA, McNutt NS, Bogdany JK, Albino AP. Expression of the mast cell growth factor interleukin-3 in melanocytic lesions correlates with an increased number of mast cells in the perilesional stroma: implications for melanoma progression. J Cutan Pathol. 2006;23:495–505.CrossRef Reed JA, McNutt NS, Bogdany JK, Albino AP. Expression of the mast cell growth factor interleukin-3 in melanocytic lesions correlates with an increased number of mast cells in the perilesional stroma: implications for melanoma progression. J Cutan Pathol. 2006;23:495–505.CrossRef
41.
go back to reference Ribatti D, Vacca A, Ria R, et al. Neovascularisation, expression of fibroblast growth factor-2, and mast cells with tryptase activity increase simultaneously with pathological progression in human malignant melanoma. Eur J Cancer. 2003;39:666–74.CrossRefPubMed Ribatti D, Vacca A, Ria R, et al. Neovascularisation, expression of fibroblast growth factor-2, and mast cells with tryptase activity increase simultaneously with pathological progression in human malignant melanoma. Eur J Cancer. 2003;39:666–74.CrossRefPubMed
42.
go back to reference Ullah E, Nagi A, Lail R. Angiogenesis and mast cell density in invasive pulmonary adenocarcinoma. J Cancer Res Ther. 2012;8:537.CrossRefPubMed Ullah E, Nagi A, Lail R. Angiogenesis and mast cell density in invasive pulmonary adenocarcinoma. J Cancer Res Ther. 2012;8:537.CrossRefPubMed
43.
go back to reference Ribatti D, Ennas MG, Vacca A, et al. Tumor vascularity and tryptase-positive mast cells correlate with a poor prognosis in melanoma. Eur J Clin Invest. 2003;33:420–5.CrossRefPubMed Ribatti D, Ennas MG, Vacca A, et al. Tumor vascularity and tryptase-positive mast cells correlate with a poor prognosis in melanoma. Eur J Clin Invest. 2003;33:420–5.CrossRefPubMed
44.
go back to reference Toth-Jakatics R, Jimi S, Takebayashi S, Kawamoto N. Cutaneous malignant melanoma: correlation between neovascularization and peritumor accumulation of mast cells overexpressing vascular endothelial growth factor. Hum Pathol. 2000;31:955–60.CrossRefPubMed Toth-Jakatics R, Jimi S, Takebayashi S, Kawamoto N. Cutaneous malignant melanoma: correlation between neovascularization and peritumor accumulation of mast cells overexpressing vascular endothelial growth factor. Hum Pathol. 2000;31:955–60.CrossRefPubMed
45.
go back to reference Diggle PJ, Besag J, Gleaves T (1976) Statistical Analysis of Spatial Point Patterns. Academic Press, London, vol. 1983, pp. 354. Diggle PJ, Besag J, Gleaves T (1976) Statistical Analysis of Spatial Point Patterns. Academic Press, London, vol. 1983, pp. 354.
46.
go back to reference Ripley BD. Tests for randomness for spatial point patterns. J R Stat Soc. 1979;B41:368–74. Ripley BD. Tests for randomness for spatial point patterns. J R Stat Soc. 1979;B41:368–74.
47.
go back to reference Ribatti D, Finato N, Crivellato E, et al. Angiogenesis and mast cells in human breast cancer sentinel lymph nodes with and without micrometastases. Histopathology. 2007;51:837–42.CrossRefPubMed Ribatti D, Finato N, Crivellato E, et al. Angiogenesis and mast cells in human breast cancer sentinel lymph nodes with and without micrometastases. Histopathology. 2007;51:837–42.CrossRefPubMed
48.
go back to reference Starkey JR, Crowle PK, Taubenberger S. Mast-cell-deficient W/Wv mice exhibit a decreased rate of tumor angiogenesis. Int J Cancer. 1988;42:48–52.CrossRefPubMed Starkey JR, Crowle PK, Taubenberger S. Mast-cell-deficient W/Wv mice exhibit a decreased rate of tumor angiogenesis. Int J Cancer. 1988;42:48–52.CrossRefPubMed
49.
go back to reference Puxeddu I, Piliponsky AM, Bachelet I, Levi-Schaffer F. Mast cells in allergy and beyond. Int J Biochem Cell Biol. 2003;35:1601–7.CrossRefPubMed Puxeddu I, Piliponsky AM, Bachelet I, Levi-Schaffer F. Mast cells in allergy and beyond. Int J Biochem Cell Biol. 2003;35:1601–7.CrossRefPubMed
50.
go back to reference Norrby K. Oral administration of a nitric oxide synthase inhibitor enhances de novo mammalian angiogenesis mediated by TNF-alpha, saline and mast-cell secretion. Acta Pathol Microbiol Scand. 2000;108:496–502.CrossRef Norrby K. Oral administration of a nitric oxide synthase inhibitor enhances de novo mammalian angiogenesis mediated by TNF-alpha, saline and mast-cell secretion. Acta Pathol Microbiol Scand. 2000;108:496–502.CrossRef
51.
go back to reference Grutzkau A, Kruger-Krasagakes S, Kogel H, Moller A, Lippert U, Henz BM. Detection of intracellular interleukin-8 in human mast cells: flow cytometry as a guide for immunoelectron microscopy. J Histochem Cytochem. 1997;45:935–45.CrossRefPubMed Grutzkau A, Kruger-Krasagakes S, Kogel H, Moller A, Lippert U, Henz BM. Detection of intracellular interleukin-8 in human mast cells: flow cytometry as a guide for immunoelectron microscopy. J Histochem Cytochem. 1997;45:935–45.CrossRefPubMed
52.
go back to reference Qu Z, Liebler JM, Powers MR, et al. Mast cells are a major source of basic fibroblast growth factor in chronic inflammation and cutaneous hemangioma. Am J Pathol. 1995;147:564–73.PubMedPubMedCentral Qu Z, Liebler JM, Powers MR, et al. Mast cells are a major source of basic fibroblast growth factor in chronic inflammation and cutaneous hemangioma. Am J Pathol. 1995;147:564–73.PubMedPubMedCentral
53.
go back to reference Grutzkau A, Kruger-Krasagakes S, Baumeister H, et al. Synthesis, storage, and release of vascular endothelial growth factor/vascular permeability factor (VEGF/VPF) by human mast cells: implications for the biological significance of VEGF206. Mol Biol Cell. 1998;9:875–84.CrossRefPubMedPubMedCentral Grutzkau A, Kruger-Krasagakes S, Baumeister H, et al. Synthesis, storage, and release of vascular endothelial growth factor/vascular permeability factor (VEGF/VPF) by human mast cells: implications for the biological significance of VEGF206. Mol Biol Cell. 1998;9:875–84.CrossRefPubMedPubMedCentral
54.
go back to reference Muramatsu M, Katada J, Hattori M, Hayashi I, Majima M. Chymase mediates mast cell-induced angiogenesis in hamster sponge granulomas. Eur J Pharmacol. 2000;402:181–91.CrossRefPubMed Muramatsu M, Katada J, Hattori M, Hayashi I, Majima M. Chymase mediates mast cell-induced angiogenesis in hamster sponge granulomas. Eur J Pharmacol. 2000;402:181–91.CrossRefPubMed
55.
go back to reference Ribatti D, Ranieri G, Nico B, Benagiano V, Crivellato E. Tryptase and chymase are angiogenic in vivo in the chorioallantoic membrane assay. Int J Dev Biol. 2011;55:99–102.CrossRefPubMed Ribatti D, Ranieri G, Nico B, Benagiano V, Crivellato E. Tryptase and chymase are angiogenic in vivo in the chorioallantoic membrane assay. Int J Dev Biol. 2011;55:99–102.CrossRefPubMed
Metadata
Title
Spatial distribution of mast cells around vessels and glands in human gastric carcinoma
Authors
Diego Guidolin
Simona Ruggieri
Tiziana Annese
Cinzia Tortorella
Andrea Marzullo
Domenico Ribatti
Publication date
01-11-2017
Publisher
Springer International Publishing
Published in
Clinical and Experimental Medicine / Issue 4/2017
Print ISSN: 1591-8890
Electronic ISSN: 1591-9528
DOI
https://doi.org/10.1007/s10238-017-0452-7

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