Effect of fractionated radiotherapy on the parotid gland: an experimental study in Brazilian minipigs

Stramandinoli-Zanicotti, Roberta Targa; Sassi, Laurindo Moacir; Schussel, Juliana Lucena; Torres, María Fernanda; Funchal, Melissa; Smaniotto, Gustavo Henrique; Dissenha, J.L.; Carvalho, André Lopes

doi:10.7162/s1809-97772013000200008

Cited by 8 publications

(6 citation statements)

References 19 publications

(36 reference statements)

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“…However, large acinar cell-like clusters were observed in irradiated SMG in all three genetic models analyzed (Figures 4B, J and S3Q). Similar clusters have been noted in salivary glands of irradiated rats, and minipigs (Konings et al, 2006; Stramandinoli-Zanicotti et al, 2013). The clusters expressed differentiated acinar cell markers, including Mist1, Nkcc1, Aqp5 and IP 3 R3, suggesting that they may be functional.…”

Section: Discussionsupporting

confidence: 80%

Limited Regeneration of Adult Salivary Glands after Severe Injury Involves Cellular Plasticity

et al. 2018

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In the adult salivary glands, the origin of replacement and regenerated acinar cells remains unclear. Although many reports describe the identification of stem cells in adult salivary glands, we have shown that differentiated acinar cells can be maintained and regenerated through self-duplication. Here, we have used genetic mouse models to further investigate acinar cell replacement and regeneration during homeostasis and after injury. Under normal conditions or after duct ligation, replacement of duct and acinar cells occurs through lineage-restricted progenitors. In contrast, after irradiation, in vivo lineage tracing shows that acinar, as well as duct, cells contribute to acinar cell regeneration, revealing that cellular plasticity is involved in salivary gland repair. Our results also indicate that even after radiation damage, several cell populations have regenerative potential for restoring salivary gland function.

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Section: Discussionsupporting

confidence: 80%

Limited Regeneration of Adult Salivary Glands after Severe Injury Involves Cellular Plasticity

et al. 2018

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“…In addition to patient-reported xerostomia, which is scored using quality of life (QoL) questionnaires, RT-induced salivary gland dysfunction is verified by an objective measure of salivary gland flow rates or scintigraphic assessment of gland function [ 20 , 21 , 22 ]. Rapid RT dose-dependent loss of secretory function seems to result from a marked loss of salivary acinar epithelial cells [ 23 , 24 ], a finding that has been supported in animal studies [ 3 , 4 , 5 , 6 , 7 ]. During the first three weeks after RT, nearly all patients present with mucositis due to significant inflammatory damage to the mucosal surfaces [ 25 ].…”

Section: Clinical Presentationmentioning

confidence: 95%

“…These efforts notwithstanding, damage to surrounding tissues such as salivary glands following RT for head and neck cancer (HNC) remains a significant problem. Despite being a highly differentiated, slowly proliferating tissue, salivary glands are surprisingly sensitive to RT [ 1 ], a phenomenon attributed to disruption of the plasma membrane on secretory salivary acinar cells and apoptosis [ 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 ]. RT-induced salivary gland dysfunction results in hyposalivation (i.e., measured reduction in saliva production), xerostomia (i.e., the sensation of oral dryness), mucositis, nutritional deficiencies, oral infections and functional changes, such as difficulties with mastication, dysphagia (i.e., problems with swallowing) and loss of taste, which can significantly reduce the quality of life for afflicted patients [ 10 , 11 ].…”

Section: Introductionmentioning

confidence: 99%

Radiation-Induced Salivary Gland Dysfunction: Mechanisms, Therapeutics and Future Directions

Jasmer

Gilman

Forti

et al. 2020

JCM

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Salivary glands sustain collateral damage following radiotherapy (RT) to treat cancers of the head and neck, leading to complications, including mucositis, xerostomia and hyposalivation. Despite salivary gland-sparing techniques and modified dosing strategies, long-term hypofunction remains a significant problem. Current therapeutic interventions provide temporary symptom relief, but do not address irreversible glandular damage. In this review, we summarize the current understanding of mechanisms involved in RT-induced hyposalivation and provide a framework for future mechanistic studies. One glaring gap in published studies investigating RT-induced mechanisms of salivary gland dysfunction concerns the effect of irradiation on adjacent non-irradiated tissue via paracrine, autocrine and direct cell–cell interactions, coined the bystander effect in other models of RT-induced damage. We hypothesize that purinergic receptor signaling involving P2 nucleotide receptors may play a key role in mediating the bystander effect. We also discuss promising new therapeutic approaches to prevent salivary gland damage due to RT.

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“…This appears to be in contrast with the phenotype of the minor SGs observed post-ICI use, whereby conventional acinar cells are still present, suggesting striking differences in the reactionary abilities between major and minor SGs (3,5). The phenotype is also dissimilar to parotid SG dysfunction induced by radiation, where saliva production is lost immediately following radiation (as opposed to around 70 days post ICI commencement), and where tissue will demonstrate both fibrosis and acinar cell cluster loss (23).…”

Section: Discussionmentioning

confidence: 76%

Lack of Conventional Acinar Cells in Parotid Salivary Gland of Patient Taking an Anti-PD-L1 Immune Checkpoint Inhibitor

et al. 2020

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Background: Salivary glands (SGs) can be damaged by immune checkpoint inhibitor (ICI) therapy. In patients with ICI-induced SG dysfunction, 60% progress to fulfill classification criteria for primary Sjögren's syndrome (pSS), owing to immune foci in SGs and/or anti-SSA autoantibody positivity. We report the SG tissue analysis of a patient with SG dysfunction after treatment with a programmed death ligand-1 (PD-L1) inhibitor, compared to that of a dry mouth ("sicca") control and pSS patient.Case presentation: The patient received the PD-L1 inhibitor durvalumab (10 mg/kg, every 2 weeks by intravenous infusion) as adjuvant treatment for stage 3 non-small cell lung carcinoma, following concurrent chemo radiotherapy. At 43 weeks after 21 cycles of Durvalumab, the patient was not capable of producing unstimulated or stimulated parotid gland saliva, and a biopsy was taken. Immunohistochemical analysis showed no classical AQP5 + CK7 − acinar cell clusters (CK7 marks intercalated ducts, IDs). In contrast, the parenchyma was dominated by hybrid epithelial "structures" with ID-like morphology, containing a mixture of AQP5 + CK7 − , AQP5 − CK7 + , and AQP5 + CK7 + cells (30 structures/mm 2 ). These structures were present at lower frequencies in sicca control (2/mm 2 ) and pSS (10/mm 2 ) tissue. Hybrid structures contained proliferating (Ki67 + ) cells and senescent (p16 + ) cells. Striated ducts showed no abnormal morphology post PD-L1 treatment, in contrast to pSS tissue. PD-L1 expression was detected in the SG parenchyma following anti-PD-L1 therapy. The SG post-PD-L1 therapy further demonstrated focal lymphocytic sialadentitis, harboring disperse, and focal CD4 + T cell-rich infiltrates. CD8 + T cells were also present. In this patient, these CD4 + and CD8 + T cells were observed in-between and inside hybrid structures. CD20 + B-cells were infrequently detected following PD-L1 blockade, in contrast to their preponderance in pSS SG tissue.Conclusion: This patient lacked conventional SG acinar cells following anti-PD-L1 therapy and demonstrated presence of hybrid intercalated duct-like structures.Pringle et al. Lack of Acinar Cells With Anti-PD-L1 TherapyUnderstanding which mechanisms and dynamics underpinning this aberrant parenchyma may be crucial to understand how SG dysfunction post ICI therapy, and potentially other affected organs. Furthermore, although the patient treated with anti-PD-L1 antibody examined here fulfills the criteria for pSS and demonstrated focal lymphocytic sialadentitis, the further histopathological characteristics do not resemble pSS.

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Effect of fractionated radiotherapy on the parotid gland: an experimental study in Brazilian minipigs

Cited by 8 publications

References 19 publications

Limited Regeneration of Adult Salivary Glands after Severe Injury Involves Cellular Plasticity

Limited Regeneration of Adult Salivary Glands after Severe Injury Involves Cellular Plasticity

Radiation-Induced Salivary Gland Dysfunction: Mechanisms, Therapeutics and Future Directions

Lack of Conventional Acinar Cells in Parotid Salivary Gland of Patient Taking an Anti-PD-L1 Immune Checkpoint Inhibitor

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