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Key Points: Question: Is the long-term efficacy of adjuvant 3-cycle carboplatin, etoposide, and vincristine (CEV) regimen considered noninferior to the standard 6-cycle CEV regimen in patients with pathologically high-risk retinoblastoma? Findings: In this noninferiority randomized clinical trial of 187 patients with a median follow-up of 79.0 months, 5-year disease-free survival for patients receiving 3-cycle and 6-cycle CEV was 90.4% and 89.2%, respectively. The difference met the noninferiority margin criterion of 12%. Meaning: A 3-cycle CEV regimen demonstrated noninferiority compared with a 6-cycle approach and was and proved to be an efficacious adjuvant chemotherapy regimen for individuals diagnosed with pathologically high-risk retinoblastoma. Importance: Adjuvant therapy is an important and effective treatment for retinoblastoma. However, there is a lack of head-to-head clinical trials comparing 3 vs 6 cycles of CEV chemotherapy (carboplatin, etoposide, and vincristine) for enucleated unilateral retinoblastoma with high-risk pathological features. Objective: To assess whether 3 cycles of CEV chemotherapy is noninferior to 6 cycles for enucleated unilateral retinoblastoma with high-risk pathological features. Design, Setting, and Participants: This double-center, randomized, open-label, noninferiority trial was conducted at 2 premier eye centers in China and included 187 patients who had undergone enucleation for unilateral retinoblastoma with high-risk pathological features (massive choroidal infiltration, retrolaminar optic nerve invasion, or scleral infiltration) between August 2013 and March 2024. The final date of follow-up was March 21, 2024. Interventions: Patients were randomly assigned to receive either 3 (n = 94) or 6 (n = 93) cycles of CEV chemotherapy regimen after enucleation. Main Outcomes and Measures: The primary end point was disease-free survival, with a noninferiority margin of 12%. Secondary end points encompassed overall survival, safety, economic burden, and the quality of life of children. Results: All 187 patients (median [IQR] age, 25.0 [20.0-37.0] months; 83 [44.4%] female) completed the trial. Median (IQR) follow-up was 79.0 (65.5-102.5) months. Five-year disease-free survival was 90.4% for the 3-cycle group vs 89.2% for the 6-cycle group (difference, 1.2% [95% CI, −7.5% to 9.8%]), which met the noninferiority criterion (P =.003 for noninferiority). The 6-cycle group experienced a higher frequency of adverse events, greater reduction in quality of life scores, and increased costs compared with the 3-cycle group. Conclusions and Relevance: Among patients with unilateral pathologic high-risk retinoblastoma, 3 cycles of CEV chemotherapy resulted in 5-year disease-free survival that was noninferior to 6 cycles of CEV chemotherapy. Trial Registration: ClinicalTrials.gov Identifier: NCT01906814 This randomized clinical trial examines whether 3 cycles of carboplatin, etoposide, and vincristine chemotherapy is noninferior to 6 cycles for enucleated unilateral retinoblastoma with high-risk pathological features. [ABSTRACT FROM AUTHOR]

Background: Idiopathic orbital inflammation (IOI) is a disfiguring and vision-threatening fibroinflammatory disorder. The pathogenesis of IOI has not been elucidated. We sought to clarify the regulatory T cell (Treg) distribution and function in patients with IOI. Methods: The frequency, phenotype and function of Tregs were identified by multicolor flow cytometry and in vitro cell functional assays. Plasma and tissue samples were obtained to investigate cytokines, chemokines and their receptors of interest by relative real-time polymerase chain reaction (PCR) and Luminex assays. Results: Compared with healthy subjects, patients with IOI exhibited obvious increases of Tregs in peripheral blood and affected orbital tissues. Circulating Tregs from patients with IOI were significantly more polarized to a Th17-like phenotype with defective regulatory function, whereas orbit-derived Tregs were polarized to a Th2-like phenotype. Furthermore, ST2 expression levels in circulating Tregs and interleukin (IL)-33 mRNA levels in orbital tissues were decreased in IOI. IL-33 restored the suppressive function of Tregs, reduced interferon (IFN)-γ production by Tregs and decreased the activation of orbital fibroblasts (OFs) cocultured with Tregs in IOI. Conclusion: Increased Tregs with proinflammatory and profibrotic polarization were first identified in IOI, suggesting that Treg plasticity and heterogeneity plays an essential role in IOI pathogenesis. Additionally, our study identified a regulatory effect of IL-33 on inflammation and fibrosis in IOI. Reversing the plastic Tregs via IL-33 might be a potential option for IOI patients. [ABSTRACT FROM AUTHOR]

Cell cycle deregulation is involved in the pathogenesis of many cancers and is often associated with protein kinase aberrations, including the polo-like kinase 1 (PLK1). We used retinoblastoma, an intraocular malignancy that lacks targeted therapy, as a disease model and set out to reveal targetability of PLK1 with a small molecular inhibitor ON-01910.Na. First, transcriptomic analysis on patient retinoblastoma tissues suggested that cell cycle progression was deregulated and confirmed that PLK1 pathway was upregulated. Next, antitumor activity of ON-01910.Na was investigated in both cellular and animal levels. Cytotoxicity induced by ON-01910.Na was tumor specific and dose dependent in retinoblastoma cells, while nontumor cells were minimally affected. In three-dimensional culture, ON-01910.Na demonstrated efficient drug penetrability with multilayer cell death. Posttreatment transcriptomic findings revealed that cell cycle arrest and MAPK cascade activation were induced following PLK1 inhibition and eventually resulted in apoptotic cell death. In Balb/c nude mice, a safe threshold of 0.8 nmol intravitreal dosage of ON-01910.Na was established for intraocular safety, which was demonstrated by structural integrity and functional preservation. Furthermore, intraocular and subcutaneous xenograft were significantly reduced with ON-01910.Na treatments. For the first time, we demonstrated targetability of PLK1 in retinoblastoma by efficiently causing cell cycle arrest and apoptosis. Our study is supportive that local treatment of ON-01910.Na may be a novel, effective modality benefiting patients with PLK1-aberrant tumors. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate patient pain and discomfort following oculoplastic surgery performed under general anesthesia and to assess key factors associated with postoperative pain and discomfort. Methods: A prospective observational cohort study was conducted among 212 consecutive patients who underwent oculoplastic surgery performed under general anesthesia. The patients were assessed according to quantified levels of pain and discomfort postoperatively. Analgesic requests were recorded, and responses were statistically analyzed. Results: Pain and discomfort after oculoplastic surgery under general anesthesia were reported by 32.1% and 28.3% of the patients, respectively; 2.8% of the patients requested analgesic medication within 18 hours after surgery. The patients who underwent orbital decompression, secondary orbital implantation, and orbital fracture repair were more likely to develop significant postoperative pain and discomfort (P<0.001), and the patients who underwent enucleation/evisceration during orbital implantation were more likely to develop postoperative discomfort (P<0.001). The predictors of pain were smoking history, prior surgery on the operative eye, and anxiety (P<0.05), and the predictor of discomfort was anxiety (P<0.05). Conclusion: Patients undergoing oculoplastic surgery tend to experience postoperative pain and discomfort. Anxiety is a risk factor for both postoperative pain and discomfort, while smoking history and prior surgery on the operative eye may be associated with postoperative pain. [ABSTRACT FROM AUTHOR]

Purpose: To compare the clinical effects of different cycles of carboplatin, etoposide, and vincristine (CEV) regimens of adjuvant chemotherapy in postenucleation high-risk patients with IRSS Stage I retinoblastoma (RB). Methods: A retrospective analysis of 53 RB patients hospitalized in the Zhongshan Ophthalmic Center of Sun Yat-sen University was performed. All patients had unilateral involvement, received enucleation treatment, were diagnosed as RB by pathology, and had high-risk pathological factors. Patients either refused postoperative chemotherapy or received three or six cycles of CEV regimen chemotherapy. The clinical information, treatment, and results of patients in all groups were compared. Results: A total of 19 cases refused postenucleation chemotherapy, 18 cases received three cycles, and 16 cases received six cycles of the CEV regimen chemotherapy. The 5-year disease-free survival rate and the overall survival (OS) rate in the chemotherapy group were higher than those in the non-chemotherapy group (97.1% vs. 63.2%, p = 0.001) and were not different between the three-cycle chemotherapy group and the six-cycle chemotherapy group (94.4% vs. 100%, p = 0.35). Conclusion: After eye enucleation for patients with high-risk unilateral RB, the CEV regimen chemotherapy was associated with a higher survival rate. The three-cycle CEV regimen adjuvant chemotherapy was effective and is expected to replace the six-cycle CEV regimen chemotherapy. [ABSTRACT FROM AUTHOR]

Aim. To study the efficacy and safety of subantimicrobial dose (SD) doxycycline(50 mg/d) in patients with active and moderate-to-severe Graves’ orbitopathy (GO). Methods. Thirteen patients with active and moderate-to-severe GO received once daily oral doxycycline (50 mg/d) for 12 wk. Treatment response at 24 wk was used as the primary outcome, measured by a composite of improvement in Clinical Activity Score (CAS), diplopia, motility, soft tissue swelling, proptosis, and eyelid aperture. Secondary outcome was the change of quality of life score (QoL, including visual functioning subscale and appearance subscale). Adverse events were also recorded. Results. Overall improvement was noted in eight out of 13 patients (61.5%, 95% CI 31.6%–86.1%). Both CAS and soft tissue swelling significantly ameliorated in eight patients at 24 wk. Five patients (38.5%) had improvement in ocular motility of ≥8 degrees. Eyelid aperture (46.2%) also decreased remarkably. For QoL, a significant improvement in appearance subscale (P=0.008) was noted during the study, whereas no difference was observed in visual functioning subscale (P=0.21). Two patients reported mild stomachache at 12 wk. Conclusions. SD doxycycline appears to be effective and safe for the treatment of active and moderate-to-severe GO. It might serve as a new promising therapeutic strategy for GO. This trial is registered with NCT01727973. [ABSTRACT FROM AUTHOR]

Single nucleotide polymorphisms (SNPs) of p53 rs1042522, MDM2 rs2279744 and p21 rs1801270, all in the p53 pathway, which plays a crucial role in DNA damage and genomic instability, were reported to be associated with cancer risk and pathologic characteristics. This case-control study was designed to analyse the association between these SNPs and retinoblastoma (RB) in a Chinese Han population. These SNPs in 168 RB patients and 185 adult controls were genotyped using genomic DNA from venous blood. No significant difference was observed in allele or genotypic frequencies of these SNPs between Chinese RB patients and controls (all P > 0.05). However, the rs1042522 GC genotype showed a protective effect against RB invasion, as demonstrated by event-free survival (HR = 0.53, P = 0.007 for GC versus GG/CC). This effect was significant for patients with a lag time >1 month and no pre-enucleation treatment (P = 0.007 and P = 0.010, respectively), indicating an interaction between p53 rs1042522 and clinical characteristics, including lag time and pre-enucleation treatment status. Thus, the rs1042522 SNP may be associated with RB invasion in the Han Chinese population; however, further large and functional studies are needed to assess the validity of this association. [ABSTRACT FROM AUTHOR]

Cell cycle deregulation is involved in the pathogenesis of many cancers and is often associated with protein kinase aberrations, including the polo-like kinase 1 (PLK1). We used retinoblastoma, an intraocular malignancy that lacks targeted therapy, as a disease model and set out to reveal targetability of PLK1 with a small molecular inhibitor ON-01910.Na. First, transcriptomic analysis on patient retinoblastoma tissues suggested that cell cycle progression was deregulated and confirmed that PLK1 pathway was upregulated. Next, antitumor activity of ON-01910.Na was investigated in both cellular and animal levels. Cytotoxicity induced by ON-01910.Na was tumor specific and dose dependent in retinoblastoma cells, while nontumor cells were minimally affected. In three-dimensional culture, ON-01910.Na demonstrated efficient drug penetrability with multilayer cell death. Posttreatment transcriptomic findings revealed that cell cycle arrest and MAPK cascade activation were induced following PLK1 inhibition and eventually resulted in apoptotic cell death. In Balb/c nude mice, a safe threshold of 0.8 nmol intravitreal dosage of ON-01910.Na was established for intraocular safety, which was demonstrated by structural integrity and functional preservation. Furthermore, intraocular and subcutaneous xenograft were significantly reduced with ON-01910.Na treatments. For the first time, we demonstrated targetability of PLK1 in retinoblastoma by efficiently causing cell cycle arrest and apoptosis. Our study is supportive that local treatment of ON-01910.Na may be a novel, effective modality benefiting patients with PLK1-aberrant tumors.

The aim of the present study was to identify mutations in the fibroblast growth factor receptor 2 (FGFR2) gene in patients with Crouzon syndrome and characterize the associated clinical features. A total of two Chinese patients diagnosed with Crouzon syndrome underwent complete examinations, including best‑corrected visual acuity, slit‑lamp, examination, fundus examination, optical coherence tomography and computed tomography of the skull. Genomic DNA was extracted from peripheral blood samples collected from the patients, as well as their family members and 200 unrelated control subjects from the same population. Exons 8 and 10 in the FGFR2 gene were amplified by polymerase chain reaction and directly sequenced. Patient #1 had a heterozygous missense mutation (c.1025G>A, p.C342Y) in exon 10 of FGFR2. Patient #2 had a heterozygous mutation (c.1084+1 G>T; IVS10+1G>T) in intron 10. The mutations were not present in any of the unaffected family members or unrelated control subjects. These findings expand the mutation spectrum of FGFR2, and are valuable for genetic counseling in addition to prenatal diagnosis in patients with Crouzon syndrome.

The current study was performed with aim to investigate the fibroblast growth factor receptor 2 (FGFR2) gene in two Chinese families with two different forms of syndromic craniosynostosis, and to characterize their associated clinical features. Two families underwent complete ophthalmic examinations, and two patients from each family were diagnosed with craniosynostosis. Genomic DNA was extracted from leukocytes of peripheral blood collected from these two families and from 200 unrelated subjects within the same population as controls. Exons 8 and 10 of the FGFR2 gene were amplified by polymerase chain reaction and directly sequenced. Ophthalmic examinations of the two patients revealed shallow orbits and ocular proptosis, accompanied by midface hypoplasia and craniosynostosis. Case 1 had retinal detachment, abnormal limbs and hands, while case 2 exhibited normal hands and feet upon clinical examination. A heterozygous FGFR2 missense mutation c.833G>T (C278F) in exon 8 was identified in these two patients, but not in unaffected family members or the normal controls. Although FGFR2 gene mutations and polymorphisms have been studied in various ethnic groups, we report a mutation of FGFR2 in two different Chinese patients with two different types of syndromic craniosynostosis.

Crouzon syndrome, a dominantly inherited disorder and the most common type of craniosynostosis syndrome, is caused by mutations in the fibroblast growth factor receptor 2 (FGFR 2) gene, and characterized by craniosynostosis, shallow orbits, ocular proptosis, midface hypoplasia and a curved, beak‑like nose. The purpose of the present study was to investigate the fibroblast growth factor receptor 2 (FGFR 2) gene in two Chinese families with Crouzon syndrome and to characterize the associated clinical features. Two families underwent complete ophthalmic examination, and three patients in two families were diagnosed with Crouzon syndrome. Genomic DNA was extracted from leukocytes of peripheral blood samples, which were collected from the family members and 200 unrelated control subjects from the same population. Exons 8 and 10 of the FGFR 2 gene were amplified using polymerase chain reaction analysis and were directly sequenced. Ophthalmic examinations, including best‑corrected visual acuity, slit‑lamp examination, fundus examination and Computerized Tomography scans, and physical examinations were performed to exclude systemic diseases. These patients were affected with shallow orbits and ocular proptosis, accompanied by midface hypoplasia, craniosynostosis, strabismus or papilloedema, with clinically normal hands and feet. A heterozygous FGFR 2 missense mutation, c.811‑812insGAG (p.273insGlu) in exon 8 was identified in the affected individual, but not in the unaffected family members or the normal control individuals in family 1. In family 2, another heterozygous FGFR 2 missense mutation, c.842A>G (P.Tyr281Cys or Y281C), in exon 8 was identified in the affected boy and his mother, but not in the unaffected family members or the normal control individuals. Although FGFR 2 gene mutations and polymorphisms have been reported in various ethnic groups, particularly in the area of osteology, the present study reported for the first time, to the best of our knowledge, the identification of two novel FGFR 2 gene mutations in Chinese patients with Crouzon syndrome.

Purpose: The purposed of this study was to investigate the fibroblast growth factor receptor 2 (FGFR2) gene in one Chinese family with Crouzon syndrome and to characterize the related clinical features., Methods: One family underwent complete ophthalmic examinations, and two patients were diagnosed with Crouzon syndrome. Genomic DNA was extracted from leukocytes of peripheral blood collected from the family and 100 unrelated control subjects from the same population. Exons 8 and 10 of FGFR2 were amplified by polymerase chain reaction (PCR) and directly sequenced. We performed ophthalmic examinations, including best-corrected visual acuity, slit-lamp examination, fundus examination, Pentacam, Goldmann perimetry, and computed tomography (CT) of the skull., Results: The two patients were affected with shallow orbits and ocular proptosis, accompanied by midface hypoplasia, craniosynostosis, and clinically normal hands and feet. A heterozygous FGFR2 missense mutation c.866A>C (Gln289Pro) in exon 8 was identified in the affected individuals, but not in any of the unaffected family members and the normal controls., Conclusions: Although FGFR2 mutations and polymorphisms have been reported in various ethnic groups, especially in the area of osteology, we report, for the first time, the identification of one new FGFR2 mutation in Chinese patients with Crouzon syndrome.

Purpose: To explore factors which lead to recurrence of idiopathic orbital inflammatory pseudotumor (IOIP)., Methods: Idiopathic orbital inflammatory pseudotumor in 209 cases between Jan 1, 1978 and Dec 31, 1999 in our hospital was evaluated retrospectively. The comparison of clinical and pathological parameters between patients with at least one episode of recurrence and those with no recurrence at all was performed and analyzed using logistic regression method., Results: Follow-up results (with a mean follow-up time of 3.4 years, ranging from 0.5 year to 21.0 years) showed that the recurrence rate of IOIP was 41%. Sex and proptosis were associated with the recurrence of IOIP. Male gender was more likely to relapse than female counterparts, with the male being 52% and female being 25%. The severer the proptosis is, the higher the rate of recurrence. Among the clinical subtypes of IOIP, the rate of recurrence (17%) in cases with dacryoadenitis was the lowest, followed by anterior local orbital mass (44%), posterior orbital mass (54%), myositis (75%) and diffuse subtype (100%). However, the clinical subtypes did not show significant relationship with the recurrence of IOIP., Conclusions: Male gender and severe proptosis are associated with a higher recurrent rate in patients with IOIP.

Purpose: To summarize the clinical manifestation of thyroid-associated ophthalmopathy (TAO) with elevated intraocular pressure (IOP), and to analyze the contributing factors., Methods: One hundred and six cases (188 eyes) of ocular hypertension in 339 cases (597 eyes) with TAO were collected from 1994 to 2001 and their clinic manifestations were summarized and analyzed., Results: It was demonstrated that the incidence of ocular hypertension in TAO was 31.3%, and was more frequently found in the male than in the female. The elevated IOP in TAO was found to be partially related to compression of the eyeball by enlarged extraocular muscles, the elevated intraorbital pressure as result of the proliferation of intraorbital connective tissue and the enlargement as well as swelling of extraocular muscles. It was also related to the severity of TAO other than the course of TAO. The ocular hypertension in most cases can be controlled with reduction of IOP by methylprednisolone or orbital decompression., Conclusion: Specific clinical features were found in TAO patients with ocular hypertension. It should be differentiated with primary glaucoma. The IOP in most cases can be controlled by prompt and effective treatment of TAO.