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Imbalance of Neutrophils
and Lymphocyte Counts
Can Be Predictive of
Hepatocellular Carcinoma
Occurrence in Hepatitis
C-related Cirrhosis Treated
With Direct-acting Antivirals
Dear Editors:
We read with interest the article published by Debes et al.1These investigators observed that, in patients with hepatitis C-related cirrhosis, the serum levels of inflammatory cytokines before treatment and their modi-fication with direct-acting antiviral (DAA) were associated with occurrence or recurrence of hepatocellular carcinoma (HCC). An additional hypothesis may be a dysregulation of the antitumor response after the sharp decrease in the hepatitis C viral load induced by DAA therapy, promoting tumor development. We evaluated whether changes in neutrophil and lymphocyte counts during treatment with DAA can be associated with HCC development. Retro-spective laboratory data obtained at baseline and at the end of treatment in 308 consecutive patients with hepatitis C-related cirrhosis, but without previous HCC, were evaluated. Patients were treated with different approved DAA regimens at different centers in the metropolitan area of Bologna, Italy, between March 2015 and August 2016. After a median follow-up of 10.5 months from the end of treatment, HCC was detected and confirmed by 2 independent imaging techniques or biopsy in 23 of 308 patients (7.24%). A significant increase in neutrophil counts (2.88 109/L ± 1.21 vs 3.32 109/L± 1.32; P ¼ .0002) and a significant decrease in lymphocyte counts (1.61 109/L ± 0.84 vs 1.46 109/L± 0.79; P ¼ .037) were observed between baseline and the end of treatment. We evaluated the difference in neutrophils and lymphocytes between baseline and the end of treatment in patients with or without HCC occur-rence. In patients with HCC development (n ¼ 23), we observed a significant increase in neutrophils (2.35 109/L ± 1.02 vs 3.11 109/L ± 1.26; P ¼ .033) and decrease in lymphocytes (1.78 109/L± 1.07 vs 0.99 109/L ± 0.53; P ¼ .003) during treatment. In patients without HCC development (n ¼ 285), there was a similar trend, but it was not statistically significant (neutrophils: 3.00 109/L± 1.26 vs 3.23 109/L ± 1.41 [P ¼ .08]; lymphocytes: 1.66 109/L± 0.86 vs 1.54 109/L± 0.85 [P¼ .14]).
It is well-known that neutrophils promote adhesion and seeding of distant organ sites through the secretion of circulating growth factors such as vascular endothelial growth factor and proteases.2,3 In contrast, cytotoxic T lymphocytes play a crucial role in tumor defense inducing tumor cell death and inhibiting tumor cell proliferation and migration, thereby dictating the host’s immune response to malignancy.2 Our study suggests that, during DAA treat-ment, there is a significant imbalance between lymphocytes and neutrophils that is particularly evident in subjects developing HCC. This imbalance may result in an unfavor-able microenvironment that favors the growth of cancer cells. Thus, inflammation may induce changes in the cancer microenvironment favoring cancer progression.2Based on these observations, we suppose that treatment with DAA, in some patients, can induce the deregulation of immune de-fenses characterized by an increase of vascular endothelial growth factor, leading to an early development of HCC, as suggested by Debes et al1and by Villani et al5in a recently published study.
In this complex context, evaluation of changes in neutrophil and lymphocyte counts during treatment with DAAs adds a simple and easily to obtain information about the patient’s inflammatory state and their possible risk of developing HCC after DAA treatment. Q4
ANDREA CASADEI GARDINI Department of Medical Oncology
Istituto Scientifico Romagnolo per lo Studio e Cura dei Tumori (IRST) IRCCS
Meldola, Italy FABIO CONTI
Francesco Giuseppe Foschi Division of Internal Medicine Ospedale di Faenza
Faenza, Italy STEFANO BRILLANTI PIETRO ANDREONE
Research Centre for the Study of Hepatitis
Department of Medical and Surgical Sciences (DIMEC) University of Bologna
Bologna, Italy
and the members of Bologna DAA group
References
1. Debes JD, et al. Gastroenterology 2018;154:151–517. 2. Prieto J, et al. Nat Rev Gastroenterol Hepatol 2015;
12:681–700.
3. Rossi L, et al. Ann Surg Oncol 2015;22:1377–1384.
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Gastroenterology 2018;-:1–2 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120
4. Lai Wei, et al. J Biol Chem.
Q2 Q3
5. Villani R, et al. PLoS One 2016;11:e0167934.
Andrea Casadei Gardini and Fabio Conti contributed equally to this work. Acknowledgments
Other members of the Bologna DAA group: Giuseppe Mazzella, Federico Ravaioli, Federica Buonfiglioli, Luigi Bolondi, Cristina Crespi, Marco Lenzi,
Paolo Muratori, Gabriella Verucchi, Lorenzo Badia, Mauro Bernardi, Paolo Caraceni, Maria Cristina Morelli, Sonia Berardi.
Conflicts of interest
The authors have made the following disclosures:Stefano Brillanti: AdvisoryQ1
Board for MSD and GILEAD Sciences; Pietro Andreone: Advisory Board for MSD, GILEAD Sciences, ABBVIE, BMS, INTERCEPT; Research grant from MSD, ABBVIE, GILEAD Sciences, BMS.
https://doi.org/10.1053/j.gastro.2017.12.051
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