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  • 1
    In: Histopathology, Wiley, Vol. 74, No. 5 ( 2019-04), p. 699-708
    Abstract: The present study evaluates the impact of hypoxia‐related carbonic anhydrase IX and XII isoenzyme expression as a basic adaptive mechanism to neutralise intracellular acidosis in classical Hodgkin's lymphoma ( cHL ). Methods and results Eighty‐one primary biopsies and 15 relapsed tissue samples diagnosed with cHL were analysed for necrosis, CAIX and CAXII expression and cell proliferation to compare hypoxia‐related histological and functional data with survival characteristics. Variable, but highly selective cell membrane CAIX expression could be demonstrated in Hodgkin–Reed–Sternberg ( HRS ) cells in 39 of 81 samples (48.1%), while virtually no staining presented in their microenvironment. In contrast, CAXII expression in HRS cells could be demonstrated in only 18 of 77 samples (23.4%), with significant stromal positivity (50 of 77, 64.9%). The CAIX + positive phenotype was strongly associated with lymphocyte depletion (four of four, 100%) and nodular sclerosis (29 of 51, 56.9%) subtypes. CAIX /Ki‐67 dual immunohistochemistry demonstrated suppressed cell proliferation in CAIX + positive compared to CAIX − negative HRS cells ( P   〈  0.001). Seventy‐two months’ progression‐free survival ( PFS ) was significantly lower for the CAIX positive group (0.192) compared with the CAIX negative group (0.771) ( P   〈  0.001), while the overall survival ( OS ) did not differ ( P  = 0.097). Conclusion Hypoxic stress‐related adaptation – highlighted by CAIX expression – results in cellular quiescence in HRS cells, potentially contributing to the short‐term failure of the standard chemotherapy in cHL .
    Type of Medium: Online Resource
    ISSN: 0309-0167 , 1365-2559
    URL: Issue
    RVK:
    Language: English
    Publisher: Wiley
    Publication Date: 2019
    detail.hit.zdb_id: 2006447-0
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  • 2
    In: International Journal of Molecular Sciences, MDPI AG, Vol. 21, No. 14 ( 2020-07-15), p. 5001-
    Abstract: The inhibition of cancer-related carbonic anhydrase (CA) activity is a promising way to intensify anti-tumor responses. In vitro data suggest improved efficacy of cytotoxic drugs in combination with CA-inhibitors in several cancer types. Despite accumulating data on CA-expression, experimental or clinical studies towards B-cell lymphoma therapy are missing. We therefore decided to test the effect of the CA-inhibitor acetazolamide (AA) on the conventional CHOP treatment regimen using the A20/BalbC in vivo syngeneic mouse lymphoma model. Tumor growth characteristics, 18F-MISO-PET activity, histomorphology, cell proliferation, and T-cell immune infiltrate were determined following single or multiple dose combinations. All results point to a significant increase in the anti-tumor effect of CHOP+AA combinations compared with the untreated controls or with the single CHOP or AA treatments. CD3+ and CD8+ T-cell immune infiltrate increased 3–4 times following CHOP+AA combination compared with the classical CHOP protocol. In conclusion, CA-inhibitor AA seems to act synergistically with the anti-tumor treatment CHOP in aggressive lymphoma. Further to a cytotoxic effect, AA and other more selective blockers potentially support tumor-associated immune responses through the modification of the microenvironment. Therefore, CA-inhibitors are promising candidates as adjuvants in support of specific immunotherapies in lymphoma and other malignancies.
    Type of Medium: Online Resource
    ISSN: 1422-0067
    Language: English
    Publisher: MDPI AG
    Publication Date: 2020
    detail.hit.zdb_id: 2019364-6
    SSG: 12
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