Artificial intelligence-based differential diagnosis of orbital MALT lymphoma and IgG4 related ophthalmic disease using hematoxylin-eosin images.

PURPOSE: To investigate the possibility of distinguishing between IgG4-related ophthalmic disease (IgG4-ROD) and orbital MALT lymphoma using artificial intelligence (AI) and hematoxylin-eosin (HE) images. METHODS: After identifying a total of 127 patients from whom we were able to procure tissue blocks with IgG4-ROD and orbital MALT lymphoma, we performed histological and molecular genetic analyses, such as gene rearrangement. Subsequently, pathological HE images were collected from these patients followed by the cutting out of 10 different image patches from the HE image of each patient. A total of 970 image patches from the 97 patients were used to construct nine different models of deep learning, and the 300 image patches from the remaining 30 patients were used to evaluate the diagnostic performance of the models. Area under the curve (AUC) and accuracy (ACC) were used for the performance evaluation of the deep learning models. In addition, four ophthalmologists performed the binary classification between IgG4-ROD and orbital MALT lymphoma. RESULTS: EVA, which is a vision-centric foundation model to explore the limits of visual representation, was the best deep learning model among the nine models. The results of EVA were ACC = 73.3% and AUC = 0.807. The ACC of the four ophthalmologists ranged from 40 to 60%. CONCLUSIONS: It was possible to construct an AI software based on deep learning that was able to distinguish between IgG4-ROD and orbital MALT. This AI model may be useful as an initial screening tool to direct further ancillary investigations.

Stromal area differences with epithelial-mesenchymal transition gene changes in conjunctival and orbital mucosa-associated lymphoid tissue lymphoma.

Purpose: To examine the molecular biological differences between conjunctival mucosa-associated lymphoid tissue (MALT) lymphoma and orbital MALT lymphoma in ocular adnexa lymphoma. Methods: Observational case series. A total of 129 consecutive, randomized cases of ocular adnexa MALT lymphoma diagnosed histopathologically between 2008 and 2020.Total RNA was extracted from formalin-fixed paraffin-embedded tissue from ocular adnexa MALT lymphoma, and RNA-sequencing was performed. Orbital MALT lymphoma gene expression was compared with that of conjunctival MALT lymphoma. Gene set (GS) analysis detecting for gene set cluster was performed in RNA-sequence. Related proteins were further examined by immunohistochemical staining. In addition, artificial segmentation image used to count stromal area in HE images. Results: GS analysis showed differences in expression in 29 GS types in primary orbital MALT lymphoma (N=5,5, FDR q-value <0.25). The GS with the greatest difference in expression was the GS of epithelial-mesenchymal transition (EMT). Based on this GS change, immunohistochemical staining was added using E-cadherin as an epithelial marker and vimentin as a mesenchymal marker for EMT. There was significant staining of vimentin in orbital lymphoma (P<0.01, N=129) and of E-cadherin in conjunctival lesions (P=0.023, N=129). Vimentin staining correlated with Ann Arbor staging (1 versus >1) independent of age and sex on multivariate analysis (P=0.004). Stroma area in tumor were significant difference(P<0.01). Conclusion: GS changes including EMT and stromal area in tumor were used to demonstrate the molecular biological differences between conjunctival MALT lymphoma and orbital MALT lymphoma in ocular adnexa lymphomas.

Relationship between vitreous interleukin-6 levels and vitreous particles findings on widefield optical coherence tomography in posterior uveitis.

PURPOSE: To investigate relationship between vitreous interleukin-6 levels and vitreous particles findings on widefield optical coherence tomography in posterior uveitis. METHODS: This retrospective study examined vitreous inflammatory cells (hyperreflective particles) of posterior uveitis on widefield optical coherence tomography (WOCT). We examined the number of hyperreflective particles (possibility of vitreous inflammatory cells) observed on WOCT and the correlations with interleukin-6 (IL-6) levels. The relationship between vitreous IL-6 levels and image findings from WOCT from 37 eyes (34 patients) with posterior uveitis were analyzed. Mean patient age was 63.4±15.7 years. (Mean± standard deviation) IL-6 concentration in vitreous humor was 79.9±7380.9 pg/mL Uveitis was infectious in 9 cases and non-infectious in 28 cases with multiplex polymerase chain reaction system. We measured the number and size of vitreous cells in the posterior vitreous, defined as the space between the upper vitreous and the internal limiting membrane on WOCT at the macular, upper, and lower regions. Image analysis software was also used for cell counting. RESULTS: A strong correlation was seen between human and software counts. Pearson's correlation coefficient (PCC) was performed to compare categorial variables (on macular +0.866; upper cavity +0.713; lower cavity +0.568; total vitreous cavity +0.834; P<0.001 each). IL-6 levels correlated with both vitreous cell counts and cell counts observed on macular WOCT (human-counted group +0.339, P = 0.04; software-counted group +0.349, P = 0.03). Infectious uveitis showed higher IL-6 levels (P = 0.016) and high cell counts compared with non-infectious uveitis (P = 0.04). CONCLUSIONS: Vitreous number of hyperreflective particles (cells) findings on WOCTcorrelated well with human and software cell counts. Vitreous cells findings on WOCT also correlated with IL-6 concentrations on macular.

Machine Learning Model with Texture Analysis for Automatic Classification of Histopathological Images of Ocular Adnexal Mucosa-associated Lymphoid Tissue Lymphoma of Two Different Origins.

PURPOSE: The purpose of this study was to develop artificial intelligence algorithms that can distinguish between orbital and conjunctival mucosa-associated lymphoid tissue (MALT) lymphomas in pathological images. METHODS: Tissue blocks with residual MALT lymphoma and data from histological and flow cytometric studies and molecular genetic analyses such as gene rearrangement were procured for 129 patients treated between April 2008 and April 2020. We collected pathological hematoxylin and eosin-stained (HE) images of lymphoma from these patients and cropped 10 different image patches at a resolution of 2048 × 2048 from pathological images from each patient. A total of 990 images from 99 patients were used to create and evaluate machine-learning models. Each image patch of three different magnification rates at ×4, ×20, and ×40 underwent texture analysis to extract features, and then seven different machine-learning algorithms were applied to the results to create models. Cross-validation on a patient-by-patient basis was used to create and evaluate models, and then 300 images from the remaining 30 cases were used to evaluate the average accuracy rate. RESULTS: Ten-fold cross-validation using the support vector machine with linear kernel algorithm was identified as the best algorithm for discriminating between conjunctival mucosa-associated lymphoid tissue and orbital MALT lymphomas, with an average accuracy rate under cross-validation of 85%. There were ×20 magnification HE images that were more accurate in distinguishing orbital and conjunctival MALT lymphomas among ×4, ×20, and ×40. CONCLUSION: Artificial intelligence algorithms can successfully distinguish HE images between orbital and conjunctival MALT lymphomas.

En-face widefield optical coherence tomography angiography for understanding vascular networks changes in two cases of acute retinal necrosis.

PURPOSE: The present study assesses the utility of en-face widefield optical coherence tomography angiography (OCTA) imaging for evaluating the retinal vascular network during the course of treatment in acute retinal necrosis(ARN). OBSERVATIONS: OCTA images of two cases of acute retinal necrosis were analyzed. Case 1 was a 15-year-old male with visual crowding in his right eye who had best-corrected visual acuity of 16/20 and intraocular pressure of 25 mmHg in his right eye on initial evaluation. Case 2 was a 57-year-old male with visual crowding in his left eye who had best-corrected visual acuity of 20/20 in his left eye on initial examination and intraocular pressure of 19.3 mmHg. In both patients, dynamic changes could be tracked by en-face ultra-widefield OCTA imaging before and up to 1 year after surgical treatment. The images showed arteriovenous anastomosis and the nonperfused area on the surface of the retina. CONCLUSIONS AND IMPORTANCE: En-face widefield OCTA is useful for monitoring the structure of retinal vessels over time in acute retinal necrosis. Wide-angle OCTA is used to non-invasively examine retinal vascular dynamic changes in ARN. OCTA artifacts due to intraocular inflammation appeared, making interpretation difficult. These will remain as issues in the future. It seems difficult for a while to completely replace FA due to the problem of image clarity.

Relationship between Vitreous IL-6 Levels, Gender Differences and C-Reactive Protein (CRP) in a Blood Sample of Posterior Uveitis.

This study retrospectively determined the relationship between vitreous IL-6 levels and clinical and laboratory data collected from uveitis patients. We examined an unknown cause of posterior uveitis, collecting vitreous fluid to investigate vitreous IL-6 levels. The samples were analyzed in consideration of clinical and laboratory factors, such as the male/female ratio. The present study included 82 eyes from 77 patients with a mean age of 66.20 ± 15.41 years. The IL-6 concentrations of the vitreous specimens were 6255.0 ± 14,108.3 pg/mL in males and 277.6 ± 746.3 pg/mL in females, which was found to be a statistically significant difference (p = 0.048) (n = 82). There was also a statistically significant correlation between vitreous IL-6 concentrations, serum C-reactive protein (CRP) value and white blood cell counts (WBCs) (n = 82). In multivariate analysis, vitreous IL-6 levels were significantly correlated with gender and CRP in all cases (p = 0.048 and p < 0.01, respectively) and were also significantly correlated with CRP in non-infectious uveitis (p < 0.01). In infectious uveitis, there were no significant differences between IL-6 level and several variables. Vitreous IL-6 concentrations were higher in males than in females in all cases. In non-infectious uveitis, vitreous IL-6 levels were correlated with serum CRP. These results might suggest that intraocular IL-6 levels depend on gender differences in posterior uveitis, and intraocular IL-6 levels in non-infectious uveitis may reflect systemic inflammations, including increased serum CRP.

Relationship between ultra-widefield optical coherence tomography and ophthalmoscopy for detecting posterior inflammation in posterior uveitis and panuveitis.

PURPOSE: To confirm the utility of ultra-widefield optical coherence tomography (W-OCT) for diagnosing uveitis. METHOD: We retrospectively studied patients who had been diagnosed with uveitis and had undergone W-OCT. All patients had visited at Osaka Metropolitan University between January 2019 and January 2022. On W-OCT, vitreous opacity ("W-OCT VO") and the presence of vitreous cells ("W-OCT Cells") were identified by three specialists. We compared findings from ophthalmoscopy ("Ophthalmoscopic findings") and fluorescein angiography ("FAG findings") with those from W-OCT. RESULTS: This study investigated 132 eyes from 68 patients (34 males, 34 females; mean age, 53.97±22.71 years). Vitreous cells in posterior uveitis and panuveitis differed significantly between "W-OCT Cells" and "Ophthalmoscopic findings" for all cases (P = 0.00014). Vitreous opacities in posterior uveitis and panuveitis did not differ significantly between "W-OCT VO" and "Ophthalmoscopic findings" (P = 0.144) for all cases. Compared to "Ophthalmoscopic findings", "W-OCT Cells" offered 51.1% sensitivity and 66.7% specificity for all cases (p<0.01). Compared to "Ophthalmoscopic findings", "W-OCT VO" offered 78.6% sensitivity and 30% specificity for all cases (p = 0.19). In addition, "W-OCT Cells" did not differ significantly from "FAG findings" for all cases (P = 0.424). CONCLUSION: W-OCT was shown to offer significantly greater sensitivity than ophthalmoscopy for detecting vitreous cells. The results of this study may add an option for the evaluation of uveitis.

En Face Images Using Ultra-Widefield Optical Coherence Tomography in 2 Cases of Traumatic Hypotony Maculopathy before and after Surgical Intervention.

The aim was to investigate the structural changes of the retina using en face ultra-widefield optical coherence tomography (OCT) images during the treatment of hypotony maculopathy with traumatic cyclodialysis. Case 1 was a 43-year-old male patient with visual crowding in his left eye (metallic wire injury that occurred 3 weeks previously) who was referred to our department. Although best-corrected visual acuity was 20/20 in his left eye on initial evaluation, intraocular pressure was 6 mm Hg. Case 2 was a 20-year-old male patient with visual crowding in his left eye (baseball ball injury that occurred 4 weeks previously) who was referred to our department. Although best-corrected visual acuity was 16/20 in his left eye on initial examination, intraocular pressure was 5 mm Hg. Surgical interventions were performed in both cases. En face ultra-widefield OCT images were able to be used to trace dynamic changes before the intervention and up to 1 year later. The images obtained in these two cases made it possible to confirm the progress from wrinkles on the surface of the retina to normalization of vascular structure and improvement of ellipsoid zone disruption. En face ultra-widefield OCT is useful for monitoring multilayer structures of the retina in hypotony maculopathy cases.

Safety and efficacy of 27-gauge transconjunctival vitrectomy for the diagnosis of posterior uveitis or pan uveitis of unknown origin.

BACKGROUND: Diagnostic vitrectomy is an important method for evaluating uveitis, and its diagnostic utility is high regardless of whether the uveitis is infectious or non-infectious. The course of diagnostic vitreous surgery with 27-gauge pars plana vitrectomy and perioperative complications is reported. METHODS: An observational retrospective study of patients who underwent 27-gauge diagnostic vitrectomy due to atypical intraocular inflammation was conducted. The final diagnosis rate, complications due to surgery, preoperative visual acuity, and postoperative visual acuity (1 month and 6 months after surgery) were examined retrospectively. RESULTS: Diagnostic vitreous surgery was performed in 32 patients and 35 eyes (14 males and 18 females, age 14-85 years, median 67 years) during the study period. The average operation time was 52 min for 19 eyes with cataract surgery and 35 min for 16 eyes without cataract surgery. Preoperative log(minimum angle of resolution [MAR]) visual acuity was 0.84 ± 0.87, 1-month postoperative logMAR visual acuity was 0.41 ± 0.55 (p = 0.004, n = 28), and 6-month postoperative average logMAR visual acuity was 0.45 ± 0.73 (p = 0.012, n = 15). The diagnosis was made by diagnostic vitrectomy in 19 cases (54%). Postoperative complications were observed in 2 of 35 postoperative patients (5%); one involved increased intraocular pressure, and the other case involved vitreous hemorrhage of the eye, necessitating reoperation. CONCLUSION: Diagnostic 27-gauge vitrectomy could be effective for evaluating intraocular inflammation.

FOXP3 and CXCR4-positive regulatory T cells in the tumor stroma as indicators of tumor immunity in the conjunctival squamous cell carcinoma microenvironment.

Conjunctival squamous cell carcinoma (SCC) is the most common ocular surface neoplasia. The purpose of this retrospective study was to examine the role of regulatory T cell (Treg) activity in tumor immunity and investigate the tumor microenvironment as a new treatment focus in conjunctival SCC. Cancer progression gene array and immunohistochemical analyses of FOXP3 as a Treg marker, CD8 as a tumor-infiltrating lymphocyte marker, and CXCR4 expression on activated Tregs were conducted in a series of 31 conjunctival SCC cases. The objective was to investigate the immunoreactive response in tumor cells and stromal cells in the cancer microenvironment. The stroma ratio in tumor cells was investigated by monitoring α-smooth muscle actine (SMA) expression between carcinoma in situ (Tis) and advanced carcinoma (Tadv) (P<0.01). No significant change in PD-L1 expression was observed in this study (P = 0.15). Staining patterns of FOXP3, CD8, and CXCR4 were examined separately between tumor cells and stromal cells in SCC tumors. Differences in staining of FOXP3 in Tregs and CD8 in tumor-infiltrating lymphocytes in tumor stroma in the Tis group were observed compared with the Tadv group (each P<0.01). In addition, double immunostaining of CXCR4/FOXP3 was correlated with progression-free survival (P = 0.049). Double immunostaining of CXCR4/FOXP3 correlated with American Joint Committee on Cancer T-stage, independent of age or Ki67 index (P<0.01). Our results show that FOXP3 and the CXCR4/FOXP3 axis are important pathologic and prognostic factors of ocular surface neoplasia, including SCC. The tumor microenvironment of conjunctival SCC should be considered in the future development of treatment options.

Insights into Current Management Strategies for Dysthyroid Optic Neuropathy: A Review.

Dysthyroid optic neuropathy (DON) is a potentially sight-threatening eye disease associated with Graves' orbitopathy (GO). DON is not common in GO patients, reportedly occurring in only about 5% of patients. The pathogenesis of severe DON is considered to involve both muscular nerve strangulation and impaired blood flow. There is some objective grading of physical examination findings and the severity of GO, including a clinical activity score (CAS) and EUropean Group On Graves' Orbitopathy (EUGOGO), but no specialized protocol completely characterizes DON. Most clinicians have decided that the combination of clinical activity findings, including visual acuity, color vision, and central critical fusion frequency, and radiological findings, including magnetic resonance imaging (MRI), can be used to diagnose DON. MRI has the most useful findings, with T2-weighted and fat-suppressed images using short-tau inversion recovery (STIR) sequences enabling detection of extraocular changes including muscle and/orbital fat tissue swelling and inflammation and, therefore, disease activity. The first-choice treatment for DON is intravenous administration of steroids, with or without radiotherapy. Unfortunately, refractoriness to this medical treatment may indicate the need for immediate orbital decompression within 2 weeks. Especially in the acute phase of DON, thyroid function is often unstable, and the surgeon must always assume the risk of general anesthesia and intra- and post-operative management. In addition, there are currently many possible therapeutic options, including molecular-targeted drugs. The early introduction and combination of these immunomodulators, including Janus kinase inhibitors and insulin-like growth factor-1 receptor antibody (teprotumumab), may be effective for GO with DON. However, this is still under investigation, and the number of case reports is small. It is possible that these options could reduce systemic adverse events due to unfocused glucocorticoid administration. The pathophysiology of DON is not yet fully understood, and further studies of its treatment and long-term visual function prognosis are needed.

EPIDERMAL GROWTH FACTOR RECEPTOR EXPRESSION IN A CASE OF FOCAL NODULAR GLIOSIS OF THE RETINA.

PURPOSE: To describe the immunohistochemical profile in a case with focal nodular gliosis (FNG) of the retina. METHODS: A 56-year-old female patient presented with vitreoretinal tractional syndrome with FNG of the retina. After resection of the retinal tumor tissue during the 25-G pars plana vitrectomy, immunohistochemistry using anti-epidermal growth factor receptor (EGFR), p-53, Ki67, glial fibrillary acid protein (GFAP), CD34, and vascular endothelial growth factor antibodies was performed in the excised tissue of the FNG of the retina. RESULTS: Histopathological analysis of the tumor led to a diagnosis of FNG of the retina. Spindle cells of the tumor exhibited strong positive staining for glial fibrillary acid protein, and there was local staining for CD34 in the endothelial cells in the blood vessels. The epidermal growth factor receptor and vascular endothelial growth factor immunoreactivity were strongly observed in the endothelial cells. CONCLUSION: This study demonstrated epidermal growth factor receptor expression in eyes with FNG of the retina. Oncogenic epidermal growth factor receptor might trigger and amplify the expression and function of endothelial vascular endothelial growth factor.

Two Cases of Extremely High-IL-6 Pan-uveitis with Subretinal Exudation and Cell Migration.

PURPOSE: To describe two cases of extremely high-IL-6 pan-uveitis with subretinal exudation and cell migration. METHODS: Pre-operative and postoperative images and IL-6 values in vitreous samples of two pan-uveitis cases were analyzed. RESULTS: Case 1 was a 76-year-old man with blurry vision in his right eye. Fundus examination and optical coherence tomography showed vitreous opacification with vitreous cells and the presence of a white-yellowish retinal exudate with peripheral choroidal detachment all around. The IL-6 value was 16,600 pg/ml. Case 2 was a 63-year-old man with blurry vision in his right eye. On fundus examination, there was severe vitreous opacification in his right eye. The IL-6 value was 26,600 pg/ml. Importantly, there was good responsiveness to steroids and the TNF inhibitor. CONCLUSION: Unclassified intraocular inflammation might include a new category of disease with unilateral pan-uveitis with good response to steroid therapy and extremely high vitreous IL-6 values.

Visual outcomes and choroidal thickness associated with human leukocyte antigen DRB1*04 in unclassifiable uveitis in Japanese patients.

PURPOSE: Human leukocyte antigen (HLA) and immunity are related. Uveitis is also closely related to immunity. For example, the common presence of human leukocyte antigen (HLA)-DRB1*04 in the immune response is well known. The aim of this study was to investigate the relationship between visual prognosis and various HLA alleles before and after therapy in patients with unclassifiable uveitis, excluding those with Vogt-Koyanagi-Harada (VKH) disease. METHODS: This retrospective case series included 42 eyes from 22 consecutive patients with unclassifiable uveitis, excluding those with VKH disease. Visual acuity (VA), sex, refractive error, central retinal thickness (CRT), central choroidal thickness (CCT), and duration from onset to treatment were measured at initial and 6-month visits. Mean values of parameters were compared at each visit. Genotyping was performed by polymerase chain reaction amplification with sequence-specific primers. RESULTS: DRB1*04 showed a dominant change. No significant difference was observed in the other alleles. In DRB1*04, The mean differences in initial CCT, 6-month CCT, and 6-month VA showed statistically significant difference was found in best-corrected visual acuity (BCVA) between DRB1*04+ and DRB1*04- at the first visit. BCVA values at baseline and at the final visit were 0.13 ± 0.29 and 0.20 ± 0.36 in the DRB1*04+ and 0.00045 ± 0.20 and - 0.058 ± 0.11 in the DRB1*04- groups(p = 0.00465). Central Choroidal Thickness (CCT) values pretreatment and at the final visit after treatment were (pretreatment:361.00 ± 361.0 µm,after treatment: 286.00 ± 106.53 µm, p = 0.0174) in the DRB1*04+ group, and (pretreatment:281.3 ± 139.68 µm,after treatment:223.85 ± 99.034 µm, p = 0.0426) in the DRB1*04- group, respectively, indicating changes between baseline and the final visit. CCT was significantly greater in the DRB1*04+ group at both the initial visit and at 6 months. Multivariate analysis showed a significant difference between the presence or absence of DRB1*04 and sex. CONCLUSION: HLA-DRB1*04 allele may affect visual prognosis and CCT in unclassifiable uveitis.

Expression of thrombospondin-1 in conjunctival squamous cell carcinoma is correlated to the Ki67 index and associated with progression-free survival.

PURPOSE: Conjunctival squamous cell carcinoma (SCC) is primarily treated with surgical resection. SCC has various stages, and local recurrence is common. The purpose of this study was to investigate thrombospondin-1 expression and its association with prognosis. METHODS: In this retrospective study, a gene expression array along with immunohistochemistry were performed for the evaluation of thrombospondin-1 expression, localization, as well as Ki67 labeling cell indices in carcinoma in situ (Tis) and advanced conjunctival SCC (Tadv). The presence or absence and intensity of cytoplasmic and nuclear staining in tumor cells were also divided into groups with a score of 0-3 and semi-quantitatively analyzed to investigate intracellular staining patterns. The association between thrombospondin-1 expression and tumor progression in a series of 31 conjunctival SCCs was further investigated. RESULTS: All 31 patients in the cohort (100%) were East Asian. A simple comparison between Tis and Tadv demonstrated significant differences in expressions of 45 genes, including thrombospondin-1 (p < 0.01). In this cohort, 30/31 tumors were positive (96%) for thrombospondin-1. Furthermore, thrombospondin-1 intracellular staining pattern analysis scores were 2.12 and 0.96 for nuclear and cytoplasmic staining, respectively, with a significant difference observed between Tis and Tadv (p < 0.01). Alteration of the Ki67 labeling index was significantly correlated with that of the thrombospondin-1 cytoplasmic score (p = 0.030). Furthermore, univariate Cox regression analysis showed a significant correlation between thrombospondin-1 staining and progression-free survival (p = 0.026) and final orbital exenteration (p = 0.019). CONCLUSIONS: The present results demonstrated that thrombospondin-1 is a potential molecular target in the pathology of conjunctival SCC, in addition to serving as a prognostic factor.

Clinical benefit for clinical sequencing using cancer panel testing.

BACKGROUND: Clinical sequencing using a panel of genes has recently been applied worldwide for patients with refractory solid tumors, but the significance of clinical sequencing using gene panel testing remains uncertain. Here we sought to clarify the feasibility and utility of clinical sequencing in the treatment of refractory tumors at our hospital. METHODS: A total of 39 patients with advanced solid tumors treated at our hospital between 2018 and 2020 were enrolled in the clinical sequencing. Among them, we identified 36 patients whose tissue samples were of suitable quality for clinical sequencing, and we analyzed the genomic profiles of these tumors. RESULTS: Pathogenic alterations were detected in 28 (78%) of the 36 patients. The most common mutation was TP53 (55%), followed by KRAS (22%), and the highest frequency of gene amplification was ERBB2 (17%). Nine of the 36 patients were identified as candidates for novel molecular-targeted therapy based on their actionable gene alterations, but only one case ended up receiving novel targeted therapy following the genetic tests. CONCLUSIONS: Our current results suggested that clinical sequencing might be useful for the detection of pathogenic alterations and the management of additional cancer treatment. However, molecular target based on actionable genomic alteration does not always bridge to subsequent therapy due to clinical deterioration, refusal for unapproved drug, and complexity of clinical trial access. Both improved optimal timing of clinical sequencing and a consensus about its off-label use might help patients receive greater benefit from clinical sequencing.

Rapid Regression of Scleral Melting Associated with Tumor Necrosis Factor-α in a Case of Surgically Induced Necrotizing Scleritis.

PURPOSE: To report a case with rapid regression of scleral melting associated with tumor necrosis factor-α (TNF-α) in a surgically induced necrotizing scleritis (SINS) patient treated with local steroid therapy. CASE PRESENTATION: An 85-year-old male patient presented with conjunctival tumor in his right eye. Complete resection of the tumor lesion and conjunctival re-construction were performed. Local steroid drops were administered until 1 month after surgery, and a good clinical course was achieved. However, after stopping the local steroid, scleral melting to the uvea occurred on the center of the tumor-resected sclera. After diagnosing SINS, we immediately restarted his local steroid. After 2 weeks, there was a complete and rapid regression of the scleral melting. Following this episode, only local steroid therapy was continued for the treatment of SINS, with no recurrence observed after 6 months. Histopathological analysis revealed the infiltration of inflammatory cells during the acute phase, with TNF-α immune reactivity observed in the center of the melting site near the resected conjunctiva. CONCLUSION: We speculate that the observed changes were associated with the TNF-α that was present during the pathological state of SINS. Local steroid therapy may play a key role in the local immune balance in SINS.

Expression, intracellular localization, and mutation of EGFR in conjunctival squamous cell carcinoma and the association with prognosis and treatment.

PURPOSE: Conjunctival squamous cell carcinoma (SCC) is primarily treated with surgical resection. SCC has various stages, and local recurrence is common. The purpose of this study was to determine molecular localization of epidermal growth factor receptor (EGFR) and the possibility of EGFR as a biomarker for the management of conjunctival SCC. METHODS: In this retrospective study, we performed immunohistochemistry to evaluate EGFR expression and localization in tumor cells, EGFR mutation-specific expression (E746-A750del and L858R), and human papillomavirus expression in a series of 29 conjunctival SCCs. RESULTS: All 29 tumors in our cohort were EGFR positive (100%). Twenty-one of 29 tumors (72%) showed focal EGFR staining, and seven (28%) showed diffuse EGFR staining. In addition, we calculated the percentages of the two most important mutations in EGFR (exon 19 746-A750del (8/29, 27.5%), exon 21 (L858R mutant (2/29, 6.8%)) in conjunctival SCCs. We observed that the translocation of EGFR from the membrane into the cytoplasm was related to clinical prognosis, as we detected correlations between EGFR cytoplasmic staining and final orbital exenteration and between decreased EGFR membrane staining and progression-free survival. CONCLUSIONS: EGFR is important in the pathology of ocular surface squamous neoplasia including SCC and is a prognostic factor. Increased understanding of EGFR mutations may have important implications for future treatment options.

Preoperative clinical factors and visual outcomes following orbital decompression with dysthyroid optic neuropathy.

BACKGROUND: To investigate preoperative clinical factors and visual outcomes of Japanese patients with dysthyroid optic neuropathy (DON) after urgent orbital decompression. METHODS: This retrospective, observational case series study investigated 44 patients who exhibited several preoperative clinical factors that might be associated with the need for urgent orbital decompression due to DON. Additionally, the visual acuity of DON patients was compared between the patients preoperatively and at 1 and 6 months postoperatively. RESULTS: All 44 patients received steroid and with or without radiation therapy, with 27 patients able to avoid undergoing urgent surgery. However, the remaining 17 patients required urgent orbital decompression following a lack of response to the therapy. None of the patients who initially avoided surgery required additional surgery for DON. Factors significantly associated with the need for urgent orbital decompression surgery included: female gender, older age, long disease duration, unilateral significant DON, history of resistance to pulsed steroid therapy, unstable thyroid function, high TRAb (Thyrotrophin receptor antibody)value, poor visual acuity, presence of central diplopia, and presence of corneal problems (P < 0.05 each). The results also showed that postoperative visual outcomes of surgery for DON were acceptable. CONCLUSION: This study revealed several preoperative clinical factors for DON that appear to be associated with the need for urgent orbital decompression surgery in Japanese patients.