The Evaluation of Ocular Toxicity of Chemotherapy

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Review Article Iran J Ped Hematol Oncol.

2024, Vol 14, No 4, 300-309

The Evaluation of Ocular Toxicity of Chemotherapy Drugs

Seyed Mojtaba Sohrevardi PhD1, Morteza Zangeneh Soroush PhD2, Hamid Owliaey MD*3,
Elnaz Sheikhpour PhD4
1. Department of Pharmacotherapy, Facullty of Pharmacy, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
2. Department of Biomedical Engineering, Science and Research Branch, Islamic Azad University, Tehran, Iran
3. Department of Forensic Medicine & Clinical Toxicology, Yazd Branch, Islamic Azad University, Yazd, Iran
4. Hematology and Oncology Research center, Shahid Sadoughi hospital, Shahid Sadoughi University of Medical Sciences,
Yazd, Iran
*Corresponding author: Dr. Hamid Owliaey, Department of Forensic Medicine & Clinical Toxicology, Yazd Branch,
Islamic Azad University, Yazd, Iran. Email: [email protected], ORCID ID: 0000-0001-5642-9584

Received: 5 January 2024 Accepted: 16 June 2024

Abstract
Cancer continues to pose a substantial global health burden and remains one of the leading causes of mortality
worldwide. Encouragingly, survival rates have consistently improved, largely due to advancements in diagnosis
and treatment. The development of anticancer drugs, including cytotoxic chemotherapy, hormonal agents, and
targeted therapies, has significantly enhanced the efficacy of cancer treatments.
Chemotherapy-induced ocular toxicity encompasses a wide range of disorders, influenced by the eye's unique
anatomical and physiological characteristics. The mechanisms of these drugs can lead to systemic and ocular
side effects, including cytotoxicity, inflammation, and neurotoxicity. While ocular side effects from targeted
therapies are less common, they can be severe, disabling, and potentially irreversible. In some cases, immediate
discontinuation of the drug may be necessary to prevent vision-threatening complications.
Understanding these ocular side effects is crucial for early recognition and intervention by ophthalmologists and
oncologists to prevent blindness. Additionally, anticipating treatment-related toxicities enables pharmacists to
develop strategies that minimize or mitigate these side effects.
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This review focuses on the ocular toxicity associated with the most significant anticancer chemotherapeutic
agents.
Keywords: Chemotherapy, Cyclophosphamide, Ocular, Tamoxifen, Toxicity

Introduction
Cancer is a class of disorders defined by Tumors can be removed surgically,
the body's aberrant and uncontrollably whereas radiotherapy uses ionizing
dividing cells. These cancerous cells have radiation to shrink tumors and kill cancer
the capacity to spread to different tissues cells. Anticancer medications either
or organs from their original location (1- increase the cytotoxicity of cancer cells or
4). An estimated 38.4% of people are block specific pathways necessary for
expected to receive a cancer diagnosis at cancer progression. These medications are
some point in their lives, according to the integral to cancer therapy, either as
US National Cancer Institute (5). Patients standalone treatments or in combination.
and their families bear severe financial and However, cytotoxic anticancer drugs target
psychological costs as a result (6). Despite rapidly dividing cancer cells, and they can
these obstacles, improvements in diagnosis also damage healthy cells, particularly in
[ DOI: 10.18502/ijpho.v14i4.16603 ]

and treatment have led to a noteworthy the vascular, neurological, immune, and
20% increase in survival rates over the muscular systems. Additionally, the
past three decades (5- 7). Cancer treatment delicate balance of the ocular surface is
commonly involves a combination of vulnerable to chemotoxicity, leading to
approaches, including tumor-removal inflammatory, neurological, and cytotoxic
surgery, hormonal agents, anticancer effects (7).
medications, and radiation therapy.
Sohrevardi et al

Although some studies have reviewed the patients have noted occurrences of visual
ocular surface side effects, understanding disturbances and conjunctivitis as side
the underlying mechanisms remains effects (8).
limited. In addition, due to high prevalence Busulfan
of cancer in our country (3), it is Busulfan, an alkylating agent with
necessary to review such a study, myeloablative properties, inhibits DNA
therefore, this study aims to investigate replication by inducing DNA crosslinking,
ocular toxicity of chemotherapy drugs. leading to cell apoptosis. It is employed as
Anticancer drug a preparative regimen before
Cancer therapies can be broadly divided hematopoietic stem cell transplantation
into three categories: (1) hormonal agents; due to its cytotoxic effects on host
(2) conventional cytotoxic chemotherapy, hematopoietic stem and progenitor cells.
which causes cell death and reduces tumor Busulfan infusion has been linked to dry
burden by interfering with DNA synthesis eyes (keratoconjunctivitis sicca) in patients
and cellular division; and (3) the more undergoing treatment for chronic myeloid
recent molecularly targeted therapies, leukemia and other myeloproliferative
which are more precisely designed to disorders (9, 10).
target specific cellular functions in cancer 5-Fluorouracil (5-FU)
cells rather than normal cells. Molecularly 5-Fluorouracil, also known as 5-FU, is a
targeted therapies have become integral in chemotherapy drug used to treat various
systemic treatments across various cancer cancers. It is FDA-approved for gastric
types, operating through mechanisms adenocarcinoma, pancreatic
distinct from traditional cytotoxic adenocarcinoma, breast adenocarcinoma,
chemotherapy by targeting cellular and colorectal adenocarcinoma. 5-FU
signaling and angiogenesis pathways functions by inflicting damage to DNA,
crucial for tumor growth (7). In this article, especially the p53 gene, which is essential
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we aim to explain the ocular side effects of for controlling the course of the cell cycle
the most important chemotherapy drugs. and the response to DNA damage. More
Cyclophosphamide than 50% of colorectal cancers, the p53
Cyclophosphamide is used alone or in gene is overexpressed. Ocular side effects
combination with other anticancer drugs to associated with 5-FU include blurred
treat leukemias, malignant lymphomas, vision, swelling around the eyes, eye pain,
and various solid tumors, including breast sensitivity to light, excessive tearing,
cancer, testicular cancer, small cell lung conjunctivitis, eyelid inflammation,
carcinoma, neuroblastoma, and Ewing's corneal inflammation, scar formation on
sarcoma. Patients receiving the eyelid, eyelid adhesion, and rarely
cyclophosphamide, particularly those with narrowing of the tear ducts. A study
breast cancer, may experience ocular reported that half of the patients using 5-
symptoms such as dry eyes FU developed defects in the outer layer of
(keratoconjunctivitis sicca), inflammation the cornea, which resolved after several
of the eyelids and conjunctiva weeks (8, 10). In a separate study, the
(blepharoconjunctivitis), and reversible estimated prevalence rates of ocular
excessive tearing (8, 9). surface lesions associated with systemic 5-
[ DOI: 10.18502/ijpho.v14i4.16603 ]

Ifosfamide fluorouracil use were reported as follows:


Ifosfamide is a chemotherapy medication ocular irritation, 5.8%; conjunctivitis,
utilized to treat various cancers such as 3.8%; keratitis, 3.8%; tearing, 26.9%; and
bladder cancer, ovarian cancer, small cell blurred vision, 11.5% (11).
lung cancer, and osteosarcoma. Certain

Iran J Ped Hematol Oncol. 2024, Vol 14, No 4, 300-309 301

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provided that the original author and source are credited.
The Evaluation of Ocular Toxicity of Chemotherapy Drugs

Capecitabine months, for all cancer patients undergoing


Capecitabine, utilized in the treatment of interferon treatment to promptly detect any
colorectal cancer, gastric cancer, and signs of retinal toxicity (11).
breast cancer, frequently in combination Cytarabine
with docetaxel, has been associated with Cytarabine is a medication used in the
adverse effects on the ocular surface. management and treatment of leukemias
These side effects encompass reduced and lymphomas, belonging to the
vision clarity, corneal deposits, eye antimetabolic group of medications. This
discomfort, narrowing of the tear ducts, review explores its indications, action, and
inflammation of the conjunctiva, and contraindications, focusing on its role as a
inflammation of the eyelids (12). crucial agent in treating acute myeloid
Interferon leukemia and other leukemias. The
Interferon is a chemotherapeutic mechanism of action, adverse event
medication used to treat renal cell profile, and other key considerations
carcinoma, non-Hodgkin's lymphoma, (including off-label uses, dosing,
malignant melanoma, multiple myeloma, pharmacodynamics, pharmacokinetics,
and chronic myelogenous leukemia (13), monitoring, and relevant interactions)
and is also widely employed in the relevant to healthcare professionals
management of chronic hepatitis. Ocular involved in leukemia treatment are
complications such as cotton wool spots highlighted (14). The main adverse effect
and splinter hemorrhages in the retina were of cytarabine is hematologic toxicity,
noted in 42% of patients receiving which can range in severity based on
interferon. Earlier research indicated that dosage and treatment regimen. High doses
retinal hemorrhages were found in 24% of (3 g/m2) of systemic cytarabine in
patients, and among these cases, 66% also leukemia patients have been associated
exhibited cotton wool spots. These retinal with corneal toxicity. Specifically, patients
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findings typically resolve gradually with have reported painful keratitis with fine
treatment cessation. Additionally, one case opacities in the corneal epithelium shortly
study documented the development of after starting treatment, which typically
vitiligo in a patient during the eighth week resolves within a week after stopping the
of interferon alpha-2a therapy for active medication. Moreover, two leukemia
chronic hepatitis C (13). Interferon is patients in remission experienced
known to cause retinopathy. This significant bilateral vision loss following
condition typically presents with retinal combined chemotherapy, CNS irradiation
hemorrhages and cotton wool spots in the prophylaxis, and intrathecal cytarabine
posterior fundus, although it generally administration (14).
preserves visual function. However, there Methotrexate
is a risk of macular edema, which can lead Methotrexate (MTX) is an anticancer
to decreased visual acuity in some cases. medication used to treat various malignant
Patients with cancer who are diseases. It functions as a therapeutic
asymptomatic may also develop ischemic agent for treating both cancers and
retinopathy produced by interferon. Many autoimmune conditions, acting through
times, these alterations in the retina are chemotherapy and immunosuppression
[ DOI: 10.18502/ijpho.v14i4.16603 ]

reversible when interferon medication is (13). In addition, it can be administered


stopped. Therefore, regular dilated orally or through injection and acts by
fundoscopy is essential at baseline and blocking the action of dihydrofolate
during follow-up, ideally every three reductase, leading to a reduction in purine

302 Iran J Ped Hematol Oncol. 2024, Vol 14, No 4, 300-309

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provided that the original author and source are credited.
Sohrevardi et al

and thymine nucleotides. This inhibition Mitomycin C


disrupts DNA, RNA, and protein Systemically, mitomycin C is utilized for a
synthesis, primarily affecting cells in the S variety of small tumors by inhibiting
phase of the cell cycle and particularly carbonic anhydrase and ATPase in cells
targeting rapidly dividing cells (13). (13). When combined with other agents, it
Ocular complications associated with may offer palliative benefits for patients
MTX use include reduced tear production, with breast, gastric, or pancreatic
changes to the optic nerve and retina, carcinomas (8). However, topical
conjunctivitis, sensitivity to light, application of mitomycin C can lead to
development of cataracts, and excessive serious ocular complications (13).
tearing (10). Systemic administration of mitomycin C
Pemetrexed has been associated with blurred vision.
When treating advanced or metastatic non- Rubinfeld et al. documented several cases
small cell lung cancer, pemetrexed is given of severe vision-threatening complications
intravenously (15, 16). It can also be used following the use of mitomycin C eye
in conjunction with cisplatin to treat drops after pterygium surgery. Ocular side
malignant pleural mesothelioma that is effects included intense pain, photophobia,
incurable. Research has shown that 1% to severe secondary glaucoma, corneal edema
5% of individuals may encounter and perforation, scleral calcification, and
heightened tear production and may sudden onset of cataract. These cases
develop eye surface issues like suggest that certain pre-existing conditions
conjunctivitis as adverse effects of or high cumulative dosages may elevate
pemetrexed (16). the risk of corneal or scleral ulceration.
Suramin sodium Delayed epithelial healing and reduced
By inhibiting some autocrine growth vascularity of the sclera and cornea are
factors, suramin sodium is used to treat potential explanations for the ocular
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adrenocortical carcinoma and metastatic toxicity associated with this medication


prostate cancer (8). Ocular side effects (8).
associated with this medication include Taxanes
sensitivity to light, swelling of the Taxanes are widely used chemotherapy
conjunctiva, swelling of the eyelids, agents for various solid malignancies,
inflammation of the iris, optic nerve functioning as microtubule inhibitors that
damage, and a specific type of corneal induce cell cycle arrest and activate
opacity (9, 10). According to research by apoptosis. They are essential in treatment
Hemady et al., 16.6% of patients treated regimens for breast, ovarian, non-small
with suramin sodium developed eye- cell lung, and head and neck cancers (17).
related symptoms, with 11.4% Ocular side effects linked to taxanes
experiencing bilateral corneal deposits include conjunctival and eyelid pain, dry
resembling whirls, along with sensations eye (18, 19), epiphora, CME, and optic
of having a foreign body in the eye and neuropathy (20), nasolacrimal and lacrimal
increased tear production. These duct obstruction (18, 21), erosive
symptoms improved with the use of conjunctivitis, punctate keratopathy (22),
lubricating eye drops. Furthermore, 6.2% corneal lesions (23), chalazion, and
[ DOI: 10.18502/ijpho.v14i4.16603 ]

of patients experienced a change towards chalazion, corneal disorders (24), and


farsightedness (13). limbal stem cell deficiency (18). Taxanes
rarely affect intraocular tissues like the
lens and vitreous. Kuwata et al. (25) found
that injecting paclitaxel into newborn rats

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provided that the original author and source are credited.
The Evaluation of Ocular Toxicity of Chemotherapy Drugs

led to apoptotic changes in lens epithelial Venetoclax


cells and degeneration of lens fibers within Venetoclax inhibits the BCL-2 protein,
seven days (18). Taxane-induced macular promoting apoptosis via mitochondrial
edema usually presents with impaired pathways. It is mainly used for
visual acuity. Kaya et al. (26) studied 202 hematological malignancies, particularly
patients on taxane-based therapy and acute myeloid leukemia. Its primary side
identified cystoid macular edema (CME) effects are myelosuppression and tumor
in one patient treated with paclitaxel, lysis syndrome, with no documented
resulting in a total incidence of 0.5% (1 ocular side effects (34).
out of 202) (18). Docetaxel and paclitaxel Cetuximab
are key members of the taxane class used The monoclonal antibody cetuximab is
to treat various cancers. Studies (27-29) approved for the treatment of metastatic
indicate that docetaxel is effective for colorectal cancer, metastatic non-small cell
gastric, prostate, non-small cell lung, head lung cancer, and metastatic head and neck
and neck cancers, and locally advanced cancer. It targets the epidermal growth
breast cancer. Research has also shown factor receptor (EGFR), which is typically
nasolacrimal canaliculus occlusion in overexpressed in cancer cells. It functions
breast cancer patients receiving docetaxel by preventing the spread and growth of
(30-32), with weekly docetaxel treatment tumors. Patients receiving cetuximab for
associated with higher rates of excessive colorectal cancer treatment have reported
tearing (33). experiencing bilateral corneal erosions
Temozolomide (36).
Temozolomide, an alkylating agent Bevacizumab
approved for melanoma, anaplastic Bevacizumab, a monoclonal antibody that
astrocytoma, and glioblastoma, has good blocks vascular endothelial growth factor
penetration across the blood-retinal barrier (VEGF), is employed alongside other
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and generally exhibits a favorable side- anticancer medications for treating


effect profile. No ocular toxicity has been metastatic colorectal cancer, metastatic
noted (34). non-small cell lung cancer, advanced renal
Rituximab cell carcinoma, stage IV glioblastoma,
Rituximab is used to treat refractory relapsed or metastatic cervical cancer, and
rheumatoid arthritis, chronic lymphocytic advanced hepatocellular carcinoma (37).
leukemia (the most common adult Although ocular hyperemia has been noted
leukemia), and non-Hodgkin's lymphoma on the surface of the eye, the more critical
(either alone or in combination with other concerns involve adverse effects affecting
therapies). the posterior segment of the eye (9, 37).
It targets the surface-presented CD20 Doxorubicin
antigen on B-cells. It is also prescribed in Doxorubicin, an anthracycline antibiotic
the US for diseases such acute B-cell (38-43), is often used in combination with
leukemia in children, pemphigus vulgaris, other chemotherapy agents to treat various
certain vasculitides, and Burkitt's cancers such as ovarian cancer, non-
lymphoma (35). Ocular adverse effects Hodgkin's lymphoma, sarcoma, breast
that may arise from taking Rituximab cancer, and acute leukemia. Ocular surface
[ DOI: 10.18502/ijpho.v14i4.16603 ]

include burning in the eyes, lacrimation, effects commonly linked to doxorubicin


conjunctivitis, and in rare cases, loss or treatment include conjunctivitis and
impairment of eyesight (9). excessive tearing (epiphora) (44).
Research indicates that ocular side effects

304 Iran J Ped Hematol Oncol. 2024, Vol 14, No 4, 300-309

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provided that the original author and source are credited.
Sohrevardi et al

related to intravenous doxorubicin are anomalies were observed three weeks after
infrequent, with only a small percentage of the start of therapy and went away entirely
patients experiencing symptoms like when the tamoxifen (8) was stopped.
increased tearing and conjunctivitis (8). Furthermore, there are notable adverse
Mitotane effects of tamoxifen on the optic nerve,
Mitotane is the sole approved medication retina (retinopathy), and lens (cataracts)
for managing advanced adrenocortical (9).
carcinoma and for postoperative adjuvant Plant alkaloids
therapy. Its primary action involves Vinca alkaloids, such as vincristine,
destroying the adrenal cortex, which vinblastine, vindesine, and vinorelbine are
disrupts steroid hormone production, widely used in oncology as antineoplastic
although the precise molecular mechanism drugs, either alone or in combination with
remains uncertain. Nonetheless, certain polychemotherapy. These agents exert
confounding factors in in vitro their cell cycle-dependent action by
experiments might diminish the inhibiting tubulin polymerization into
applicability of specific studies (45). microtubules. Ocular toxicity associated
Ocular adverse effects are rare but can with these plant alkaloids includes cranial
include impaired vision, diplopia, lens nerve palsies, optic neuropathy and
opacities, toxic retinopathy with atrophy, cortical blindness, and night
papilledema, and retinal hemorrhage. blindness. A recent study demonstrated
Systemic side effects are common in optic neuropathy in three patients after a
patients receiving mitotane (14). cumulative 48 mg dose of vincristine,
Tamoxifen presenting with poor visual acuity and
For the majority of instances of metastatic optic disc pallor. One case of bilateral
breast cancer, tamoxifen, an estrogen optic atrophy resulted in blindness.
antagonist, is seen to be the best course of Additionally, night blindness was observed
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action. By decreasing the number of in a melanoma patient, and transient


cytoplasmic receptors and causing cortical blindness occurred in three
competitive inhibition at the receptor children treated for leukemia (8).
location, it prevents estradiol from Vincristine and vinblastine work by
attaching to its intended tissues. Studies blocking metaphase and disrupting the
reported on two patients who took 30 mg mitotic spindle. These medications are
of tamoxifen every day for nine to fourteen usually given through intravenous
months, developing retinopathy and administration and are advised to be used
temporary vision impairment. alongside other anticancer drugs for
In addition, 4 out of 63 patients receiving conditions such as Hodgkin's disease, non-
20 mg of tamoxifen daily (total dose of Hodgkin lymphomas, Ewing's sarcoma,
14.4 gm) with a median treatment period malignant melanoma, neuroblastomas, and
of 35 months showed signs of impaired rhabdomyosarcomas. The likelihood of
visual acuity, bilateral macular edema, neurotoxic effects increases with the
retinal yellow-white spots, and corneal dosage administered (9).
opacities. With the exception of retinal Melphalan
opacities, all ocular abnormalities were Nitrogen mustard's phenylalanine
[ DOI: 10.18502/ijpho.v14i4.16603 ]

shown to be reversible upon stopping derivative is melphalan, sometimes


medication. According to finding of one referred to as L-phenylalanine mustard.
study, two patients receiving low-dose Melphalan is a bifunctional alkylating
tamoxifen experienced bilateral optic agent that exhibits activity against specific
neuritis and retinal hemorrhage. These types of human cancers. It has FDA

Iran J Ped Hematol Oncol. 2024, Vol 14, No 4, 300-309 305

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provided that the original author and source are credited.
The Evaluation of Ocular Toxicity of Chemotherapy Drugs

approval for nonresectable ovarian constriction as potential eye-related


epithelial carcinoma and multiple adverse effects linked with this medication
myeloma palliative therapy (44). (8).
Melphalan hydrochloride intravitreous Fludarabine
injections are becoming more widely used Fludarabine, used for lymphoproliferative
in the treatment of vitreous seeding of disorders, rarely causes ocular toxicity.
retinoblastoma. These injections can cause However, opportunistic eye infections and
retinal abnormalities as well as toxic varicella-zoster virus reactivation
effects on the anterior segment of the eye. involving acute retinal necrosis have been
They also seem to occur more frequently reported (34).
in the injection meridian where the drug Obinutuzumab
concentration is highest (45). Obinutuzumab may have more adverse
Cisplatin effects than rituximab due to a stronger
Cisplatin is a chemotherapy drug (46-55). cytokine release, including higher rates of
It is a chemical containing heavy metal neutropenia and severe infections; though
that has been used for a long time to treat no significant ocular side effects have been
non-Hodgkin lymphoma, upper observed (34).
gastrointestinal malignancies, testicular,
lung, and ovarian cancer. It can be Conclusion
administered intravenously or Ocular toxicities induced by
intratracheally, and it is frequently used in chemotherapeutic agents are typically
conjunction with other chemotherapeutics unavoidable; hence, clinicians should
such paclitaxel, docetaxel, remain vigilant regarding potential vision-
cyclophosphamide, 5-fluorouracil, and threatening complications. Timely
Carmustine (BCNU). consultation with an ophthalmologist can
Since cisplatin is known to cause facilitate early detection, accurate
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neurotoxicity, reports of high dose and diagnosis, and appropriate therapeutic


cumulative dosage regimens have included interventions. Adjusting the dosage or
cases of nonspecific impaired vision, discontinuing implicated drugs may
papilledema, unilateral and bilateral mitigate the severity and duration of side
retrobulbar neuritis, and optic neuritis. effects. Therefore, healthcare professionals
High-dose intravenous regimens are more treating cancer patients should be aware of
likely to cause transient cortical blindness, the potential ocular and visual side effects
transient homonymous hemianopsia, and of common chemotherapeutic drugs. More
retinal pigmentary alterations. However, research is needed to understand the
all of these toxicities are reversible, except mechanisms behind these ocular side
the pigmentary alterations (56). effects, as current studies often do not
Oxaliplatin explore this fully.
Palliative care for testicular cancer,
advanced colon and rectal cancer,
Acknowledgements
recurrent non-Hodgkin's lymphoma,
No applicable
advanced ovarian and esophageal cancer,
and metastatic or locally advanced
[ DOI: 10.18502/ijpho.v14i4.16603 ]

pancreatic cancer are among the conditions


for which oxaliplatin is used. Research has
pinpointed hyperlacrima, conjunctivitis,
reduced visual acuity, and visual field

306 Iran J Ped Hematol Oncol. 2024, Vol 14, No 4, 300-309

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Sohrevardi et al

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