Perivascular expression of CXCL9 and CXCL12 in primary central nervous system lymphoma: T-cell infiltration and positioning of malignant B cells.

Primary central nervous system lymphomas (PCNSL) are aggressive malignancies confined to the CNS, mostly of diffuse large B-cell histotype. Despite improved understanding of the malignant B cells, little is known on the tumor microenvironment and on the response of the adaptive immunity against PCNSL. We investigated the phenotype of tumor infiltrating lymphocytes (TILs), and the expression of chemokines that could affect malignant B cells and trafficking of TILs. TILs and chemokine expression were evaluated by immunohistochemistry and in situ hybridization. Furthermore, we performed in vitro migration assays to analyze the migratory capacity of lymphocytes and malignant B cells toward chemokines and chemokine heterocomplexes. We show in 22 cases of PCNSL from immunocompetent patients that CD8(+) T cells represent the majority of TILs in the tumor mass. They tend to accumulate in perivascular areas, show Granzyme B expression and proliferate in situ. Their localization and density correlates with the expression of the inflammatory chemokine CXCL9, which is transcribed and translated by perivascular macrophages and pericytes in the perivascular microenvironment. Moreover, CXCL9 and CXCL12 are coexpressed on the tumor vasculature and form heterocomplexes. In the presence of CXCL9, CXCL12-induced migration is enhanced not only on CXCR4(+)/CXCR3(+)/CD8(+) T cells but also on CXCR4(+)/CXCR3(-) malignant B cells. These findings indicate the presence of a strong chemoattractant stimulus in the perivascular microenvironment, which might serve as regulator for the recruitment of TILs and for the angiocentric positioning of malignant B cells in the perivascular cuff.

B cell zone reticular cell microenvironments shape CXCL13 gradient formation.

Through the formation of concentration gradients, morphogens drive graded responses to extracellular signals, thereby fine-tuning cell behaviors in complex tissues. Here we show that the chemokine CXCL13 forms both soluble and immobilized gradients. Specifically, CXCL13+ follicular reticular cells form a small-world network of guidance structures, with computer simulations and optimization analysis predicting that immobilized gradients created by this network promote B cell trafficking. Consistent with this prediction, imaging analysis show that CXCL13 binds to extracellular matrix components in situ, constraining its diffusion. CXCL13 solubilization requires the protease cathepsin B that cleaves CXCL13 into a stable product. Mice lacking cathepsin B display aberrant follicular architecture, a phenotype associated with effective B cell homing to but not within lymph nodes. Our data thus suggest that reticular cells of the B cell zone generate microenvironments that shape both immobilized and soluble CXCL13 gradients.

A novel non-thermal resection tool in endoscopic management of scarred polyps.

Background and study aims Scarred polyps are challenging to resect using conventional endoscopic mucosal resection (EMR) techniques. The aim of this pilot study was to assess the feasibility of the EndoRotor device in resecting scarred polyps arising from previous endoscopic resection attempts. Patients and methods This was a prospective pilot study of patients with scarred colonic polyps treated using EndoRotor carried out in two centers. Results A total of 19 patients were included in this study. The overall cure rate using EndoRotor was 84 %; 10 patients (52.6 %) achieved cure after one attempt and six patients (31.5 %) achieved cure after two attempts. A total of three patients who had polyp recurrence after the first EndoRotor resection were referred for either endoscopic submucosal dissection (2 patients) or surgery (1 patient) due to difficult access. There were no perforations, delayed bleeding, post-polypectomy syndrome or complications requiring surgery. Conclusions In this pilot study, the novel non-thermal device (EndoRotor) has been demonstrated to be a safe and effective technique in challenging management of scarred polyps. Further randomized controlled trials comparing this technique with APC, hot avulsion, ESD and endoscopic full-thickness resection are required to ascertain the utility of EndoRotor in the hands of non-expert endoscopists.

Erratum: A novel non-thermal resection tool in endoscopic management of scarred polyps.

[This corrects the article DOI: 10.1055/a-0838-5424.].