Development of the Saini-Hodgins Addiction Risk Potential of Games (SHARP-G) Scale: An International Delphi study.

Background and Objectives: As the gaming industry experiences exponential growth, concerns about gaming disorder (GD) also grow. It is crucial to understand the structural features of games that can interact with individual characteristics of gamers to promote GD. This research consolidates the views of an international body of panelists to create an assessment tool for gauging the addictive potential of distinct games. Methods: Utilizing the iterative and structured Delphi method, an international panel of researchers, clinicians, and people with lived experience were recruited to offer a multifaceted viewpoint on the addictive risk associated with specific structural elements in games. Two rounds of surveys facilitated consensus. Results: The panel initially included 40 members-ten from research, eight from clinical settings, and 22 with lived experiences. The second round included 27 panelists-seven from research, eight from clinical settings, and 11 with lived experiences. The study identified 25 structural features that contribute to potentially addictive gaming patterns. Discussion and Conclusions: Consensus was found for 25 features, which were distilled into a 23-item evaluation tool. The Saini-Hodgins Addiction Risk Potential of Games Scale (SHARP-G) consists of five overarching categories: 'Social,' 'Gambling-Like Features,' 'Personal Investment,' 'Accessibility,' and 'World Design.' SHARP-G yields a total score indicating level of addiction risk. A case study applying the scale to three games of differing perceived risk levels demonstrated that that score corresponded to game risk as expected. While the SHARP-G scale requires further validation, it provides significant promise for evaluating gaming experiences and products.

Masseteric Nerve Transfer for Facial Paralysis Secondary to Parotid Malignancy: A Retrospective Case Series.

Background: The objective outcomes of masseteric nerve transfer in the setting of parotid malignancy are unclear. Objective: To measure objective facial reanimation outcomes of masseteric nerve transfer in patients with parotid malignancy who underwent parotidectomy with facial nerve resection. Materials and Methods: Retrospective review of patients who underwent masseteric nerve transfer for facial paralysis secondary to parotid malignancy was carried out at a tertiary referral hospital from August 2017 to November 2021. Objective facial reanimation outcomes were analyzed using Emotrics. Minimal follow-up of 6 months was required for inclusion. Results: Eight patients (five males) with a median age of 75.5 years (range 53-91) met inclusion criteria. Fifty percent had metastatic squamous cell carcinoma, and 50% had primary parotid malignancy. Five patients underwent concomitant cancer resection with facial nerve reconstruction. Seven patients received postoperative adjuvant radiotherapy. After reinnervation, patients had improved oral commissure excursion (from 1.51 mm ±1.27 to 3.77 mm ±1.81; p < 0.01) and facial symmetry during smile. Conclusion: In this study, masseteric nerve transfer enhanced oral commissure excursion and facial symmetry during smile in patients with parotid malignancy and facial nerve resection.

Stereotactic MR-guided on-table adaptive radiation therapy (SMART) for borderline resectable and locally advanced pancreatic cancer: A multi-center, open-label phase 2 study.

BACKGROUND AND PURPOSE: Radiation dose escalation may improve local control (LC) and overall survival (OS) in select pancreatic ductal adenocarcinoma (PDAC) patients. We prospectively evaluated the safety and efficacy of ablative stereotactic magnetic resonance (MR)-guided adaptive radiation therapy (SMART) for borderline resectable (BRPC) and locally advanced pancreas cancer (LAPC). The primary endpoint of acute grade ≥ 3 gastrointestinal (GI) toxicity definitely related to SMART was previously published with median follow-up (FU) 8.8 months from SMART. We now present more mature outcomes including OS and late toxicity. MATERIALS AND METHODS: This prospective, multi-center, single-arm open-label phase 2 trial (NCT03621644) enrolled 136 patients (LAPC 56.6 %; BRPC 43.4 %) after ≥ 3 months of any chemotherapy without distant progression and CA19-9 ≤ 500 U/mL. SMART was delivered on a 0.35 T MR-guided system prescribed to 50 Gy in 5 fractions (biologically effective dose10 [BED10] = 100 Gy). Elective coverage was optional. Surgery and chemotherapy were permitted after SMART. RESULTS: Mean age was 65.7 years (range, 36-85), induction FOLFIRINOX was common (81.7 %), most received elective coverage (57.4 %), and 34.6 % had surgery after SMART. Median FU was 22.9 months from diagnosis and 14.2 months from SMART, respectively. 2-year OS from diagnosis and SMART were 53.6 % and 40.5 %, respectively. Late grade ≥ 3 toxicity definitely, probably, or possibly attributed to SMART were observed in 0 %, 4.6 %, and 11.5 % patients, respectively. CONCLUSIONS: Long-term outcomes from the phase 2 SMART trial demonstrate encouraging OS and limited severe toxicity. Additional prospective evaluation of this novel strategy is warranted.

Inflammation and Fibrosis in Orbital Inflammatory Disease: A Histopathologic Analysis.

PURPOSE: The purpose of this study was to compare the histopathologic inflammation and fibrosis of orbital adipose tissue in orbital inflammatory disease (OID) specimens. METHODS: In this retrospective cohort study, inflammation, and fibrosis in orbital adipose tissue from patients with thyroid-associated orbitopathy (TAO), granulomatosis with polyangiitis (GPA), sarcoidosis, nonspecific orbital inflammation (NSOI), and healthy controls were scored by 2 masked ocular pathologists. Both categories were scored on a scale of 0 to 3 with scoring criteria based on the percentage of specimens containing inflammation or fibrosis, respectively. Tissue specimens were collected from oculoplastic surgeons at 8 international centers representing 4 countries. Seventy-four specimens were included: 25 with TAO, 6 with orbital GPA, 7 with orbital sarcoidosis, 24 with NSOI, and 12 healthy controls. RESULTS: The mean inflammation and fibrosis scores for healthy controls were 0.0 and 1.1, respectively. Orbital inflammatory disease groups' inflammation (I) and fibrosis (F) scores, formatted [I, F] with respective p -values when compared to controls, were: TAO [0.2, 1.4] ( p = 1, 1), GPA [1.9, 2.6] ( p = 0.003, 0.009), sarcoidosis [2.4, 1.9] ( p = 0.001, 0.023), and NSOI [1.3, 1.8] ( p ≤ 0.001, 0.018). Sarcoidosis had the highest mean inflammation score. The pairwise analysis demonstrated that sarcoidosis had a significantly higher mean inflammation score than NSOI ( p = 0.036) and TAO ( p < 0.0001), but no difference when compared to GPA. GPA had the highest mean fibrosis score, with pairwise analysis demonstrating a significantly higher mean fibrosis score than TAO ( p = 0.048). CONCLUSIONS: Mean inflammation and fibrosis scores in TAO orbital adipose tissue samples did not differ from healthy controls. In contrast, the more "intense" inflammatory diseases such as GPA, sarcoidosis, and NSOI did demonstrate higher histopathologic inflammation and fibrosis. This has implications in prognosis, therapeutic selection, and response monitoring in orbital inflammatory disease.

Rubella virus-associated necrotizing granulomatous inflammation with extensive eyelid, ocular, and orbital involvement.

We present a case of cutaneous granulomatous disease associated with rubella virus in a 4-year-old girl without an identifiable immunodeficiency. In this case, a combination of anti-inflammatory, anti-viral, and anti-neutrophil therapies successfully treated vision-threatening eyelid, conjunctival, scleral, and orbital inflammation.

A Multi-Institutional Phase 2 Trial of Ablative 5-Fraction Stereotactic Magnetic Resonance-Guided On-Table Adaptive Radiation Therapy for Borderline Resectable and Locally Advanced Pancreatic Cancer.

PURPOSE: Magnetic resonance (MR) image guidance may facilitate safe ultrahypofractionated radiation dose escalation for inoperable pancreatic ductal adenocarcinoma. We conducted a prospective study evaluating the safety of 5-fraction Stereotactic MR-guided on-table Adaptive Radiation Therapy (SMART) for locally advanced (LAPC) and borderline resectable pancreatic cancer (BRPC). METHODS AND MATERIALS: Patients with LAPC or BRPC were eligible for this multi-institutional, single-arm, phase 2 trial after ≥3 months of systemic therapy without evidence of distant progression. Fifty gray in 5 fractions was prescribed on a 0.35T MR-guided radiation delivery system. The primary endpoint was acute grade ≥3 gastrointestinal (GI) toxicity definitely attributed to SMART. RESULTS: One hundred thirty-six patients (LAPC 56.6%, BRPC 43.4%) were enrolled between January 2019 and January 2022. Mean age was 65.7 (36-85) years. Head of pancreas lesions were most common (66.9%). Induction chemotherapy mostly consisted of (modified)FOLFIRINOX (65.4%) or gemcitabine/nab-paclitaxel (16.9%). Mean CA19-9 after induction chemotherapy and before SMART was 71.7 U/mL (0-468). On-table adaptive replanning was performed for 93.1% of all delivered fractions. Median follow-up from diagnosis and SMART was 16.4 and 8.8 months, respectively. The incidence of acute grade ≥3 GI toxicity possibly or probably attributed to SMART was 8.8%, including 2 postoperative deaths that were possibly related to SMART in patients who had surgery. There was no acute grade ≥3 GI toxicity definitely related to SMART. One-year overall survival from SMART was 65.0%. CONCLUSIONS: The primary endpoint of this study was met with no acute grade ≥3 GI toxicity definitely attributed to ablative 5-fraction SMART. Although it is unclear whether SMART contributed to postoperative toxicity, we recommend caution when pursuing surgery, especially with vascular resection after SMART. Additional follow-up is ongoing to evaluate late toxicity, quality of life, and long-term efficacy.

AN0025, a novel antagonist of PGE2-receptor E-type 4 (EP4), in combination with total neoadjuvant treatment of advanced rectal cancer.

PURPOSE: To assess the safety and efficacy of AN0025 in combination with preoperative radiotherapy and chemotherapy in either short course (SCRT) or long course radiotherapy (LCRT) settings for those with locally advanced rectal cancer. PATIENTS AND METHODS: Twenty-eight subjects with locally advanced rectal cancer participated in this multicenter, open-label, Phase Ib trial. Enrolled subjects received either 250 mg or 500 mg of AN0025 once daily for 10 weeks with either LCRT or SCRT with chemotherapy (7 subjects/group). Participants were assessed for safety/efficacy starting from the first dose of study drug administration and were followed for 2 years. RESULTS: No treatment-emergent adverse or serious adverse events meeting dose-limiting criteria were observed, with only 3 subjects discontinuing AN0025 treatment due to adverse events. Twenty-five of 28 subjects completed 10 weeks of AN0025 and adjuvant therapy and were evaluated for efficacy. Overall, 36.0% of subjects (9/25 subjects) achieved a pathological complete response or a complete clinical response, including 26.7% of subjects (4/15 subjects who underwent surgery) who achieved a pathological complete response. A total of 65.4% of subjects had magnetic resonance imaging-confirmed down-staging ≤ stage 3 following completion of treatment. With a median follow-up of 30 months. The 12-month disease-free survival and overall survival were 77.5% (95% confidence interval [CI]: 56.6, 89.2) and 96.3% (95% CI: 76.5, 99.5), respectively. CONCLUSIONS: Treatment with AN0025 administered for 10 weeks along with preoperative SCRT or LCRT did not appear to worsen the toxicity in subjects with locally advanced rectal cancer, was well-tolerated and showed promise in inducing both a pathological and complete clinical response. These findings suggest its activity deserves further investigation in larger clinical trials.

MRI-LINAC: A transformative technology in radiation oncology.

Advances in radiotherapy technologies have enabled more precise target guidance, improved treatment verification, and greater control and versatility in radiation delivery. Amongst the recent novel technologies, Magnetic Resonance Imaging (MRI) guided radiotherapy (MRgRT) may hold the greatest potential to improve the therapeutic gains of image-guided delivery of radiation dose. The ability of the MRI linear accelerator (LINAC) to image tumors and organs with on-table MRI, to manage organ motion and dose delivery in real-time, and to adapt the radiotherapy plan on the day of treatment while the patient is on the table are major advances relative to current conventional radiation treatments. These advanced techniques demand efficient coordination and communication between members of the treatment team. MRgRT could fundamentally transform the radiotherapy delivery process within radiation oncology centers through the reorganization of the patient and treatment team workflow process. However, the MRgRT technology currently is limited by accessibility due to the cost of capital investment and the time and personnel allocation needed for each fractional treatment and the unclear clinical benefit compared to conventional radiotherapy platforms. As the technology evolves and becomes more widely available, we present the case that MRgRT has the potential to become a widely utilized treatment platform and transform the radiation oncology treatment process just as earlier disruptive radiation therapy technologies have done.

Acellular cadaveric dermal matrix grafts for orbital wall reconstruction in patients with sinonasal malignancies.

PURPOSE: To describe the utilization of acellular cadaveric dermal matrix (ACDM) in patients undergoing orbital wall reconstruction after orbital preservation surgery for sinonasal malignancy. METHODS: Retrospective case series of seven patients with sinonasal malignancy who had orbital reconstruction with ACDM implants from January 2012 to August 2020. Orbital preservation was performed in all patients with tumor extension up to and including periorbital. The main outcome measures were implant exposure, orbital infection, diplopia in primary gaze, enophthalmos, and eyelid malposition. RESULTS: Patients ranged 37-78 years old (median: 66 years) and included 4 females and 3 males. The median follow-up time was 9 months (range 6-43 months) from the date of surgery. Squamous cell carcinoma comprised the majority of tumors with all patients needing medial wall reconstruction. Three patients received postoperative radiation therapy. No patients had any implant exposure, orbital infection, enophthalmos, or eyelid malposition. CONCLUSIONS: ACDM grafts can be used safely in orbital wall reconstruction in patients with sinonasal malignancies.

Non-visual complications of orbital cellulitis (NVCOC) in pediatric vs adult populations.

PURPOSE: There have been many publications evaluating the visual outcomes of patients treated for orbital cellulitis. The aim of this study was to evaluate non-visual complications of post-septal orbital cellulitis (NVCOC) present 30 days after discharge from index hospitalization. METHODS: This was an IRB-approved, retrospective chart review. RESULTS: Ninety patients (45 pediatric, 45 adults) were identified with OC. NVCOC were significantly more common in adult patients as compared to children (40.0% vs 15.6% respectively; p < 0.05). The most common NVCOC among children was persistent ptosis, while clinically significant scarring was most common in adults. NVCOC were less persistent in children as compared to adults with 71.4% of complications in children resolving spontaneously by 6 month follow up as compared to 11.1% adults. (p < 0.05). The only statistically significant risk factor identified for the development of NVCOC in children and adults was the presence of ICE (intracranial extension) during index hospitalization (p < 0.05) and the presence of an infected orbital implant (p < 0.05) respectively. CONCLUSIONS: Adult patients experience NVCOC complications more often than children. Furthermore, the nonvisual complications in children are more likely to resolve spontaneously than those in adults. The intracranial spread of infection is a significant risk factor for late complications in children. The presence of an orbital wall/floor implant is a significant risk factor for late complications in adults. There are many differences in the etiology, pathophysiology, and course of NVCOC in children and adults, so information on these two populations should be reported separately.

The initial experience of MRI-guided precision prone breast irradiation with daily adaptive planning in treating early stage breast cancer patients.

Background: A major challenge in breast radiotherapy is accurately targeting the surgical cavity volume. Application of the emerging MRI-guided radiotherapy (MRgRT) technique in breast radiotherapy may enable more accurate targeting and potentially reduce side effects associated with treatment. Purpose: To study the feasibility of delivering MRI-guided partial breast radiotherapy or Precision Prone Irradiation (PPI) to treat DCIS and early stage breast cancer patients. Materials and methods: Eleven patients with diagnosed DCIS or early stage breast cancer treated with lumpectomy underwent CT-based and MRI-based simulations and treatment planning in the prone position. MRI-guided radiotherapy was utilized to deliver partial breast irradiation. A customized adaptive plan was created for each delivered radiotherapy fraction and the cumulative doses to the target volumes and nearby organs at risk were determined. The CT-based and the MRI-guided radiotherapy plans were compared with respect to target volumes, target volume coverage, and dose to nearby organs. Results: All patients receiving PPI successfully completed their treatments as planned. Clinical target volume (CTV) and planning target volume (PTV) dose coverage and organs-at-risk (OAR) dose constraints were met in all fractions planned and delivered and the MRI-guided clinical target volumes were smaller when compared to those of the CT-based partial breast radiotherapy plans for these eleven patients. Conclusions: MRI-guided partial breast radiotherapy as a breast radiotherapy technology is feasible and is a potential high clinical impact application of MRgRT. PPI has the potential to improve the therapeutic index of breast radiotherapy by more accurately delivering radiation dose to the cavity target and decreasing toxicities associated with radiation to the surrounding normal tissues. Prospective clinical data and further technical refinements of this novel technology may broaden its clinical implementation.

Therapy Resistance and Disease Progression in CML: Mechanistic Links and Therapeutic Strategies.

PURPOSE OF REVIEW: Despite the adoption of tyrosine kinases inhibitors (TKIs) as molecular targeted therapy in chronic myeloid leukemia, some patients do not respond to treatment and even experience disease progression. This review aims to give a broad summary of advances in understanding of the mechanisms of therapy resistance, as well as management strategies that may overcome or prevent the emergence of drug resistance. Ultimately, the goal of therapy is the cure of CML, which will also require an increased understanding of the leukemia stem cell (LSC). RECENT FINDINGS: Resistance to tyrosine kinase inhibitors stems from a range of possible causes. Mutations of the BCR-ABL1 fusion oncoprotein have been well-studied. Other causes range from cell-intrinsic factors, such as the inherent resistance of primitive stem cells to drug treatment, to mechanisms extrinsic to the leukemic compartment that help CML cells evade apoptosis. There exists heterogeneity in TKI response among different hematopoietic populations in CML. The abundances of these TKI-sensitive and TKI-insensitive populations differ from patient to patient and contribute to response heterogeneity. It is becoming clear that targeting the BCR-ABL1 kinase through TKIs is only one part of the equation, and TKI usage alone may not cure the majority of patients with CML. Considerable effort should be devoted to targeting the BCR-ABL1-independent mechanisms of resistance and persistence of CML LSCs.

Impact of the COVID-19 breast cancer screening hiatus on clinical stage and racial disparities in New York City.

BACKGROUND: The impact of the COVID-19 mammography screening hiatus as well as of post-hiatus efforts promoting restoration of elective healthcare on breast cancer detection patterns and stage distribution is unknown. METHODS: Newly diagnosed breast cancer patients (2019-2021) at the New York Presbyterian (NYP) Hospital Network were analyzed. Chi-square and student's t-test compared characteristics of patients presenting before and after the screening hiatus. RESULTS: A total of 2137 patients were analyzed. Frequency of screen-detected and early-stage breast cancer declined post-hiatus (59.7%), but returned to baseline (69.3%). Frequency of screen-detected breast cancer was lowest for African American (AA) (57.5%) and Medicaid patients pre-hiatus (57.2%), and this disparity was reduced post-hiatus (65.3% for AA and 63.2% for Medicaid). CONCLUSIONS: The return to baseline levels of screen-detected cancer, particularly among AA and Medicaid patients suggest that large-scale breast health education campaigns may be effective in resuming screening practices and in mitigating disparities.

Efficacy of a Standardized Premedication and Therapeutic Drug Monitoring Protocol for Pegaspargase to Prevent Hypersensitivity Reactions.

OBJECTIVE: The purpose of this study was to evaluate the efficacy of a standardized premedication and therapeutic drug monitoring (TDM) protocol to prevent hypersensitivity reactions from pegaspargase infusions. Pegaspargase is an essential therapeutic agent used for the treatment of acute lymphoblastic leukemia (ALL) in pediatric patients. METHODS: This study was a retrospective cohort study conducted at Wolfson Children's Hospital, Jacksonville, Florida, and included pediatric ALL patients 0 to 21 years old. Patients were excluded if they had not received the appropriate premedication after protocol implementation or had received premedication before protocol implementation. Patients were separated into 2 groups: those who received premedication before pegaspargase infusion and those who did not. The primary endpoint was the incidence of documented hypersensitivity reactions. Observational data endpoints included incidence of silent inactivation and cost savings from reducing complicated drug substitutions. RESULTS: A total of 38 patients (50 doses in no premedication group; 80 doses in premedication group) were evaluated. There was not a significant reduction in the incidence of hypersensitivity reactions for patients receiving premedication and TDM (5.3% vs 6.4%, p = 1.0). A trend towards patients reacting earlier with more severe reactions in the post-implementation group was observed. There were no incidences of silent inactivation. Observational cost analysis predicts potential drug cost savings of $106,550.45. CONCLUSIONS: A standardized premedication protocol did not reduce the incidence of hypersensitivity reactions. Premedication to prevent hypersensitivity reactions may provide a potential drug cost savings. Further investigation is warranted to assess the efficacy of a standardized premedication and TDM protocol to prevent hypersensitivity reactions.

Benefit of adjuvant chemotherapy in node-negative T1a versus T1b and T1c triple-negative breast cancer.

PURPOSE: National comprehensive cancer network guidelines recommend delivery of adjuvant chemotherapy in node-negative triple-negative breast cancer (TNBC) if the tumor is > 1 cm and consideration of adjuvant chemotherapy for T1b but not T1a disease. These recommendations are based upon sparse data on the role of adjuvant chemotherapy in T1a and T1b node-negative TNBC. Our objective was to clarify the benefits of chemotherapy for patients with T1N0 TNBC, stratified by tumor size. METHODS: We performed a retrospective analysis of survival outcomes of TNBC patients at two academic institutions in the United States from 1999 to 2018. Primary tumor size, histology, and nodal status were based upon surgical pathology. The Kaplan-Meier plot and 5-year unadjusted survival probability were evaluated. RESULTS: Among 282 T1N0 TNBC cases, the status of adjuvant chemotherapy was known for 258. Mean follow-up was 5.3 years. Adjuvant chemotherapy was delivered to 30.5% of T1a, 64.7% T1b, and 83.9% T1c (p < 0.0001). On multivariable analysis, factors associated with delivery of adjuvant chemotherapy were tumor size and grade 3 disease. Improved overall survival was associated with use of chemotherapy in patients with T1c disease (93.2% vs. 75.2% p = 0.008) but not T1a (100% vs. 100% p = 0.3778) or T1b (100% vs. 95.8% p = 0.2362) disease. CONCLUSION: Our data support current guidelines indicating benefit from adjuvant chemotherapy in node-negative TNBC associated with T1c tumors but excellent outcomes were observed in the cases of T1a and T1b disease, regardless of whether adjuvant chemotherapy was delivered.

Microbiology of orbital cellulitis with subperiosteal abscess in children: Prevalence and characteristics of Streptococcus anginosus group infection.

PURPOSE: To evaluate the predominant pathogens and clinical course in pediatric patients with orbital cellulitis (OC) complicated by subperiosteal abscess (SPA). METHODS: This is a single-center retrospective chart review evaluating pediatric patients with OC complicated by SPA treated at a tertiary care center in the Pacific Northwest. Data were analyzed for characteristics, rates of infection, and antibiotic resistance of the predominant pathogens in pediatric patients. RESULTS: Twenty-seven children were identified with OC complicated by SPA and bacterial cultures drawn. The average age (SD) of the patients was 9.2 years (4.8), median 9.6; 15 range 5 months to 17.2 years. Seventeen (63.0%) were male. Sinusitis was present in all patients. Streptococcus species were the most common pathogen accounting for 52% (17/33) of isolates. Streptococcus anginosus group (SAG) was the predominant species and were isolated in 10 out of 27 (37%) children in the study. Twenty-one (78%) patients required surgery for the treatment of SPA. Among surgically treated patients, females tended to be younger than males (p = .068). Pediatric patients with SAG infections required more surgery than children without this isolate, 100% and 65%, respectively (p = .030). Female patients tended to have SAG infections more often than males (p = .063). CONCLUSIONS: Orbital infections caused by SAG require surgical management more often than those caused by other pathogens. Our results suggest a difference in pathogenic organisms in male and female patients with SPA. SAG is one of the most common pathogens isolated in orbital cellulitis complicated by SPA in children.

Enrichment of IGF-1R and PPARγ signalling pathways in orbital inflammatory diseases: steps toward understanding pathogenesis.

BACKGROUND: Orbital inflammatory disease (OID) encompasses a wide range of pathology including thyroid-associated orbitopathy (TAO), granulomatosis with polyangiitis (GPA), sarcoidosis and non-specific orbital inflammation (NSOI), accounting for up to 6% of orbital diseases. Understanding the underlying pathophysiology of OID can improve diagnosis and help target therapy. AIMS: To test the hypothesis that shared signalling pathways are activated in different forms of OID. METHODS: In this secondary analysis, pathway analysis was performed on the previously reported differentially expressed genes from orbital adipose tissue using patients with OID and healthy controls who were characterised by microarray. For the original publications, tissue specimens were collected from oculoplastic surgeons at 10 international centres representing four countries (USA, Canada, Australia and Saudi Arabia). Diagnoses were independently confirmed by two masked ocular pathologists (DJW, HEG). Gene expression profiling analysis was performed at the Oregon Health & Science University. Eighty-three participants were included: 25 with TAO, 6 with orbital GPA, 7 with orbital sarcoidosis, 25 with NSOI and 20 healthy controls. RESULTS: Among the 83 subjects (mean (SD) age, 52.8 (18.3) years; 70% (n=58) female), those with OID demonstrated perturbation of the downstream gene expressions of the IGF-1R (MAPK/RAS/RAF/MEK/ERK and PI3K/Akt/mTOR pathways), peroxisome proliferator-activated receptor-γ (PPARγ), adipocytokine and AMPK signalling pathways compared with healthy controls. Specifically, GPA samples differed from controls in gene expression within the insulin-like growth factor-1 receptor (IGF-1R, PI3K-Akt (p=0.001), RAS (p=0.005)), PPARγ (p=0.002), adipocytokine (p=0.004) or AMPK (p=<0.001) pathways. TAO, sarcoidosis and NSOI samples were also found to have statistically significant differential gene expression in these pathways. CONCLUSIONS: Although OID includes a heterogenous group of pathologies, TAO, GPA, sarcoidosis and NSOI share enrichment of common gene signalling pathways, namely IGF-1R, PPARγ, adipocytokine and AMPK. Pathway analyses of gene expression suggest that other forms of orbital inflammation in addition to TAO may benefit from blockade of IGF-1R signalling pathways.

The potential of tear proteomics for diagnosis and management of orbital inflammatory disorders including Graves' ophthalmopathy.

BACKGROUND: Orbital compartments harbor a variety of tissues that can be independently targeted in a plethora of disorders resulting in sight-threatening risks. Orbital inflammatory disorders (OID) including Graves' ophthalmopathy, sarcoidosis, IgG4 disease, granulomatosis with polyangiitis, and nonspecific orbital inflammation constitute an important cause of pain, diplopia and vision loss. Physical examination, laboratory tests, imaging, and even biopsy are not always adequate to classify orbital inflammation which is frequently deemed "nonspecific". Tear sampling and testing provide a potential "window" to the orbital disease process through a non-invasive technique that allows longitudinal sampling as the disease evolves. Using PubMed/Medline, we identified potentially relevant articles on tear proteomics published in the English language between 1988 and 2021. Of 303 citations obtained, 225 contained empirical data on tear proteins, including 33 publications on inflammatory conditions, 15 in glaucoma, 15 in thyroid eye disease, 1 in sarcoidosis (75) and 2 in uveitis (77,78). Review articles were used to identify an additional 56 relevant articles through citation search. In this review, we provide a short introduction to the potential use of tears as a diagnostic fluid and tool to investigate the mechanism of ocular diseases. A general review of previous tear proteomics studies is also provided, with a focus on Graves' ophthalmopathy (GO), and a discussion of unmet needs in the diagnosis and treatment of orbital inflammatory disease (OID). The review concludes by pointing out current limitations of mass spectrometric analysis of tear proteins and summarizes future needs in the field.