Neoadjuvant chemotherapy followed by transoral robotic surgery versus upfront surgery for locoregionally advanced oropharyngeal carcinoma: A propensity score matched analysis.

BACKGROUND: Transoral robotic surgery (TORS) performed after neoadjuvant chemotherapy (NAC) is a promising treatment for advanced-stage oropharyngeal carcinoma (OPSCC) able to reduce the adjuvant therapy administration rate. METHODS: A retrospective bi-centric study was conducted to analyze NAC + TORS versus upfront TORS patients. A 1:1 propensity score matching was used to compare the two groups. RESULTS: Among the 300 patients with stage III-IV OPSCC, 204 patients were matched for comparing NAC + TORS versus upfront TORS. Between the two groups, no significant difference was observed in recurrences and in survival for RFS, OS, and DSS. In the NAC + TORS p16-positive population, adjuvant therapy could be spared in 51% versus 16% in the upfront surgery cohort (p < 0.001) due to the lower frequency of pathological risk factors after NAC. CONCLUSIONS: NAC followed by TORS for locoregionally advanced OPSCC demonstrated to achieve non-inferior survival outcomes to upfront surgery, while in the p16-positive population allowed to significantly spare adjuvant therapy.

Transoral robotic vertical partial laryngectomy (hemilaryngectomy) extended to the hypopharynx.

Locally advanced laryngeal cancers treatment often involves total laryngectomy, which some patients are unwilling to undergo, even if this choice reduces their survival probability. Therefore, the objective of laryngeal oncologic surgery is not only to remove the tumor, but also to preserve the organ and its functions. To overcome these concerns, several partial laryngectomy techniques have been developed. This article describes the surgical technique and a case study of a 64-year-old male patient with locally advanced laryngeal squamous cell carcinoma who underwent vertical partial laryngectomy extending to the subglottis and hypopharynx using transoral robotic surgery (TORS) with a da Vinci Single Port surgical robot. The video and article provide a detailed description of the surgical technique, which resulted in successful tumor removal with excellent oncological and functional outcomes.

Metastatic Squamous Cell Carcinoma of the Lung Disclosed From Constipation Workup.

A palpable rectal mass associated with gastrointestinal (GI) symptoms immediately raises concern for colorectal cancer, but rarely can represent distant metastatic disease. The incidence of symptomatic colorectal metastasis from a primary lung cancer without any pulmonary symptom is extremely rare. We report a rare case of constipation as the presenting symptom in a patient ultimately found to have metastatic squamous cell carcinoma of the lung. A rectal mass was readily palpable on examination, illustrating the importance of digital rectal examination. In addition, GI clinicians should maintain a high index of suspicion when evaluating patients at risk of non-GI malignancies.

Neoadjuvant chemotherapy and transoral robotic surgery for the posterior pharyngeal wall carcinoma.

BACKGROUND: The squamous cell carcinoma (SCC) of the posterior pharyngeal wall (PPW) is associated with poor oncological outcomes based on current literature data. We reported the preliminary outcomes of a potential new treatment protocol based on neoadjuvant chemotherapy (NCT) and transoral robotic surgery (TORS). METHODS: A retrospective single-center case series was performed including a total of 20 patients diagnosed with a SCC of the PPW between October 2010 and September 2021. All patients successfully completed TORS with neck dissection after NCT. Adjuvant treatment was performed in the presence of adverse pathologic features. Loco-regional control (LRC), overall survival (OS), and disease-specific survival (DSS) were defined as the time from surgery to tumor recurrence or death, as appropriate. Survival estimates were calculated by Kaplan-Meier analysis. Surgical data and post-operative functional outcomes were also reported. RESULTS: Estimated 3-year LRC, OS, and DSS rates (95% Confidence interval) were 59.7% (39.7-89.6), 58.6% (38.7-88.8), and 69.4% (49.9-96.6). The median hospital stay was 21 days (IQR 17.0-23.5). Oral diet and decannulation were achieved after a median of 14 days (IQR 12.0-15.0). Feeding tube and tracheostomy dependence after 6 months was observed in 3 (15%) and 2 (10%) patients, respectively. CONCLUSIONS: The use of NCT followed by TORS for PPW SCC treatment appears to have good oncological and functional outcomes for both early and locally advanced cancers. Further randomized trials and site-specific guidelines are needed.

Hydroxychloroquine and Cardiotoxicity.

Hydroxychloroquine (HCQ) has been used for rheumatological diseases such as systemic lupus erythematous and rheumatoid arthritis and demonstrated to improve clinical symptoms and reduce long-term sequelae. The drug is metabolized in the liver, is primarily excreted through the kidney, and works by modulating major histocompatibility complex (MHC) and various cytokines, suppressing the immune system in the process. Prolonged administration and high dosages of HCQ have been associate with cardiotoxic effects such as bradycardia, tachycardia, QT prolongation, atrioventricular block, and cardiomyopathy. Common cardiac biopsy findings of HCQ-induced toxicity are enlarged and vacuolated cells on light microscopy along with the presence of myelinoid and curvilinear bodies on transmission electron microscopy. HCQ cardiotoxicity is not very well recognized, and there are no current guidelines for routine cardiac function monitoring from either rheumatology or cardiology societies.

Single-Port Versus Multiport da Vinci System for Transoral Robotic Surgery of Hypopharyngeal and Laryngeal Carcinoma.

OBJECTIVE: Da Vinci single port (SP) has been recently approved for transoral robotic surgery (TORS). Its characteristics make it particularly feasible for laryngeal and hypopharyngeal surgery. We report our experience comparing intra- and postoperative outcomes, technical advantages, and shortcomings of transoral laryngeal and hypopharyngeal resections performed with the da Vinci SP and the da Vinci Si/Xi systems. STUDY DESIGN: Retrospective database review. SETTING: Single academic tertiary care hospital. METHODS: Subjects included adult patients with laryngeal and hypopharyngeal carcinoma who underwent TORS between 2008 and 2022. The SP and multiport (MP) systems were compared in terms of intraoperative times, short-term postoperative outcomes, and TORS-related complications after a propensity score matching. RESULTS: A total of 185 patients were enrolled (56 SP vs 129 MP patients), and a cohort of 112 patients was analyzed after matching. The docking time was reduced in the SP group (8.84 ± 4.67 vs 6.45 ± 3.11 minutes; p = .003), as well as console time (53.91 ± 29.38 vs 42.70 ± 13.72 minutes; p = .035). Positive margins were more frequent in the MP group (52% vs 43%; p = .34). The mean decannulation time was 1.86 days longer in the SP group (p = .046). No significant differences emerged from the analysis of the duration of hospitalization, enteral feeding, and TORS-related complications. CONCLUSION: SP safety profile is comparable to that of previous models, while it showed advantages in terms of reduced docking times. Console times were also shortened due to improved maneuverability and field visualization.

Prognostic role of surgical margins in patients undergoing transoral robotic surgery after neo-adjuvant chemotherapy.

PURPOSE: To define if positive and close surgical margins are associated to worse prognosis in patients who underwent transoral robotic surgery (TORS) after neoadjuvant chemotherapy (NCT). METHODS: A retrospective cohort study was carried out at a tertiary referral center. The primary outcome was local-regional control (LRC), and the results were summarized with hazard ratios (HR) and 95% confidence intervals (CIs). RESULTS: A total of 308 patients (median age: 62.0, IQR: 55.0-68.2) were included. Univariable analysis showed a significant reduced LRC for patients with positive margins (HR = 1.82, 95% CI: 1.02-3.24). However, they were not associated with worse LRC after adjusting for adverse tumor variables (HR = 0.81, 95% CI: 0.40-1.65). ROC analysis was performed on 123 patients with negative margins (AUC: 0.54) measuring an optimal threshold of 1.25 mm (sensitivity = 60.0%; specificity = 50.5%). Univariable analysis showed non-significant differences between close and wide negative margins (HR = 1.44, 95% CI: 0.59-3.54). CONCLUSIONS: A positive surgical margin is not an independent predictor of tumor control and survival. A threshold of 1.25 mm was identified as the most appropriate to define close margins, but no difference was measured after distinguishing negative margins in close and wide margins.

Neoadjuvant chemotherapy combined with transoral robotic surgery for stage III and IV laryngeal and hypopharyngeal carcinomas.

OBJECTIVES: To analyze the oncological and functional outcomes of patients with stage III-IV laryngo-hypopharyngeal cancer who underwent neoadjuvant chemotherapy (NAC) with subsequent transoral robotic surgery (TORS). MATERIALS AND METHODS: A single-center retrospective cohort study included a total of 100 patients (median age of 67.0) affected by stage III-IV supraglottic or hypopharyngeal cancer. All patients underwent NAC followed by TORS and risk-adjusted adjuvant therapy. The primary outcome was recurrence-free survival (RFS). RESULTS: The median follow-up time was 24.0 months. Estimated 2-year (95% CI) OS, DSS, and RFS were 75% (66% - 85%), 84% (76% - 92%), and 65% (56% - 76%), respectively. Among the 11 patients who relapsed on the primary site, 3 underwent salvage total laryngectomy, 3 underwent salvage CRT, and the others receive palliation or supportive care. At 6 months from surgery, 17 patients were still tracheostomized or had a stoma retainer, while 15 were gastrostomy dependent. At the Cox multivariable analysis, the clinical stage at presentation, the number of NAC cycles, and the presence of LVI were found to be independently correlated with the RFS. CONCLUSION: This study demonstrates that NAC followed by TORS can obtain good tumor control, survival, and organ preservation rates in stage III-IV laryngo-hypopharyngeal cancer.

Cardiovascular Manifestations of Systemic Sclerosis: An Overview of Pathophysiology, Screening Modalities, and Treatment Options.

Systemic sclerosis, previously known as scleroderma, is a heterogeneous, systemic disease that is defined by its 3 pathological hallmarks: the production of autoantibodies, small vessel vasculopathy, and fibroblast dysfunction, leading to an increased deposition of extracellular matrix. We conducted a review of the available literature that covers the cardiovascular manifestations of SSc: electrical conduction abnormalities, pulmonary hypertension, pericardial disease, and atherosclerosis. Within each major category, we will discuss the definition, diagnostics, and available treatment options. Increased mortality from cardiovascular complications necessitates early screening and management. Annual screening with noninvasive modalities is encouraged. The current management of each complication generally follows the management algorithms of patients regardless of SSc status and is dependent on the severity of the patient's clinical presentation.

Incidence of Olfactory Dysfunction and Associated Factors: A Nationwide Cohort Study From South Korea.

OBJECTIVES: Olfactory dysfunction, a reduced or complete loss of the ability to smell, is gaining attention because of its substantial impact on an individual's quality of life and the possibility that it is an important sign of underlying disease. However, olfactory dysfunction is underdiagnosed in the general population due to diagnostic difficulty and unpredictable prognosis. This study aimed to evaluate the prevalence of clinically diagnosed olfactory dysfunction in South Korea by using well-organized, nationwide, population-based cohort data, and the associations between olfactory dysfunction and risk of neurodegenerative disorders. METHODS: We investigated the Korean National Health Insurance Service-National Sample Cohort for patients diagnosed with olfactory dysfunction according to the International Classification of Diseases. Annual and overall incidence and prevalence of olfactory dysfunction during 2003 to 2013 and patient characteristics were analyzed. Based on those identified patients who were later diagnosed with neurodegenerative disorder, hazard ratios (HRs) of sociodemographic factors and comorbidities associated with neurodegenerative disorder were evaluated using a Cox proportional hazard regression model. RESULTS: In total, 6296 patients were clinically diagnosed with olfactory dysfunction during the study period (524.67 patients/year). The prevalence increased annually and was higher in female patients. The incidence of neurodegenerative disorders among patients with olfactory dysfunction was 4.2% within the study period. Multivariate cox regression analysis of the patients (n = 249) revealed that diabetes mellitus (HR = 1.976) and depression (HR = 2.758) were significant risk factors. CONCLUSIONS: Olfactory dysfunction is underdiagnosed in South Korea, but it is clinically important considering the possibility of presymptom of neurodegenerative disorders. In clinical practice, we should consider its association with neurodegenerative disorders and possibly other systemic conditions.

Effectiveness of cross-linked human acellular dermal matrix in primary and revision augmentation rhinoplasty.

BACKGROUND: Among the materials used for dorsal augmentation rhinoplasty (DAR), cross-linked human acellular dermal matrix (ADM) has been claimed for its low risk of infection and extrusion. The aim of this study was to compare the effectiveness of ADM in subjects undergoing primary versus revision dorsal augmentation rhinoplasties. METHODS: Using a retrospective cohort study design, the investigators enrolled a cohort set of DAR patients operated by a single surgeon during a 65-month interval. The predictor variable was the treatment group (primary or revision DAR). The main outcome variables were postoperative changes with regard to the degree of augmentation (ratio of the dorsal height [DH] and radix height [RH] to the nasal length) and patients' and surgeons' satisfaction with the aesthetic and functional results. Other study variables were grouped into the following categories: demographic, surgical, and pathological. Descriptive, uni-, and bivariate statistics were computed using P ≤ 0.05 as a cutoff value. RESULTS: The study cohort comprised 145 subjects (75.2% with primary DAR; 39.3% females) with a mean age of 30.7 ±â€¯9.4 years (range, 19-58). DAR was linked to the significant changes in DH and RH in both the treatment groups. Comparison of the two groups revealed that there was no significant difference in DH and RH between both the groups. Surgeons' and patients' satisfaction rates were comparable between the two surgery groups, neither of which experienced serious complications. Microscopic findings of the removed ADM showed abundant collagen tissue with newly formed vessels without signs of foreign body reaction. CONCLUSION: Despite significant differences in patient characteristics (age; number of osteotomy, tip plasty, and hump reduction surgeries), the results of this study suggest that ADM can be used in both primary and revision DAR, with minimal complications.

Anticoagulation for Atrial Fibrillation: A Review of Current Literature and Views.

Atrial fibrillation is a common supraventricular tachyarrhythmia with uncoordinated atrial activation and ineffective atrial contraction. This leads to an increased risk of atrial thrombi, most commonly in the left atrial appendage, and increased risks of embolic strokes and/or peripheral thromboembolism. It is associated with significant morbidity and mortality. To meet the concerns of thrombi and stroke, anticoagulation has been the mainstay for prevention and treatment thereof. Historically, anticoagulation involved the use of aspirin or vitamin K antagonists, mainly warfarin. Since early 2010s, direct oral anticoagulants (DOACs) including dabigatran, rivaroxaban, apixaban, and edoxaban have been introduced and approved for anticoagulation of atrial fibrillation. DOACs demonstrated a dramatic reduction in the rate of intracranial hemorrhage as compared to warfarin, and offer the advantages of absolution of monitoring therefore avoid the risk of hemorrhages in the context of narrow therapeutic window and under-treatment characteristic of warfarin, particularly in high-risk patients. One major concern and disadvantage for DOACs was lack of reversal agents, which have largely been ameliorated by the approval of Idarucizumab for dabigatran and Andexanet alfa for both apixaban and rivaroxaban, with Ciraparantag as a universal reversal agent for all DOACs undergoing Fast-Track Review from FDA. In this article, we will be providing a broad review of anticoagulation for atrial fibrillation with a focus on risk stratification schemes and anticoagulation agents (warfarin, aspirin, DOACs) including special clinical considerations.

Melanocytic Nevus in the External Auditory Canal with Keratin Accumulation.

Nevus is a benign melanocytic neoplasm and the most common type of skin tumor. It may occur anywhere on the skin, but it is rare in the external auditory canal (EAC). We present a case of melanocytic nevus in the EAC with keratin accumulation. In microscopic surgery, the mass was excised completely, and the wax and keratin material medial portion of the EAC behind the mass was removed. In this patient, a melanocytic nevus in the EAC caused symptoms of hearing loss and wax and keratin buildup. For melanocytic nevus in the EAC, excision and pathologic confirmation should be performed if there are symptoms or when malignant transformation is suspected.

Effects of Adenoidectomy and Adenotonsillectomy on Tympanostomy Tube Reinsertion Based on Korean Population-Based National Sample Cohort Data.

OBJECTIVES: We evaluated the effects of adenoidectomy and adenotonsillectomy (AT) on tympanostomy tube (TT) reinsertion using population-based retrospective cohort data to confirm the association of adenoidectomy or AT with TT reinsertion reported in several previous studies. MATERIALS AND METHODS: This study used data from the National Health Insurance Service National Sample Cohort in Korea. We selected patients who underwent TT insertion between the ages of 0 and 9 years from 2006 to 2015. Patients were divided into the following groups: group 1, TT insertion only; group 2, TT insertion with adenoidectomy; and group 3, TT insertion with AT. The number of TT reinsertions was analyzed. RESULTS: There were 745 patients in group 1, 115 in group 2, and 251 in group 3. There were 1,019 cases of total TT insertion and 336 of reinsertion in group 1, 169 of total TT insertion and 31 of reinsertion in group 2, and 343 of total TT insertion and 50 of reinsertion in group 3. The rates of TT reinsertion were significantly lower in groups 2 and 3 than in group 1. The risks of TT reinsertion in groups 2 and 3 were significantly lower than the risk in group 1 in both univariate and multivariate Cox regression analysis. CONCLUSION: TT reinsertion was significantly lower in the TT insertion with adenoidectomy and TT insertion with AT groups than in the TT insertion only group. We confirmed the effects of adenoidectomy and AT on reduction of the rate of repeated TT insertion by analysis of population-based data.

Dermoid Cyst in the Postauricular Area.

Dermoid cyst is a rare benign tumor and about 7% of occurrences are found in the head and neck region. Its location is almost always in the midline of the body such as the orbit, oral cavity, and nose, but it is rarer in and around the auricle. The authors present a 31-year-old woman with dermoid cyst in the postauricular area which is a rare site for this lesion. In surgery under local anesthesia, the mass was limited to the subcutaneous area and excised completely. Surgical excision should be considered for cosmetic reasons and the mass should be excised completely to prevent recurrence and infection. Histopathologic confirmation is important and mandatory after excision to confirm the pathologic diagnosis and rule out the possibility of malignancy.

Spongiotic osteoma in the external auditory canal: Two cases of a rare tumor.

Osteoma of the external auditory canal is a rare benign tumor with an estimated incidence of 0.05% of total otologic surgeries. In most cases, an osteoma in the external auditory canal does not cause symptoms because the tumor grows slowly and does not occlude the ear canal. However, if the mass grows to occlude the external auditory canal, several symptoms can occur, including conductive hearing loss, aural fullness, and keratin debris accumulation. We present two cases of this rare tumor in a 23-year-old woman and a 19-year-old man. The mass was surgically excised at the level of the peduncle under local anesthesia with microscope assistance. The base of the excised mass was drilled with a diamond burr to remove all osseous lesions. Histopathologic findings showed spongiotic osteomas. In these cases, patients had symptoms of aural fullness, although the osteomas did not completely occlude the external auditory canal, and the symptoms improved after surgical excision without recurrence.

High Risk of Sudden Sensorineural Hearing Loss in Several Autoimmune Diseases according to a Population-Based National Sample Cohort Study.

OBJECTIVE: We investigated the risk of sudden sensorineural hearing loss (SSNHL) in patients with autoimmune diseases compared with a control group in a population-based study using a National Health Insurance Service National Sample Cohort data from Korea. METHODS: We enrolled autoimmune-disease patients who were ≥20 years of age in 2006 into the autoimmune-disease group, and selected a control group with similar demographic characteristics. We tracked the 2 groups from 2006 to 2015 and compared the proportions of patients who developed SSNHL. RESULTS: Of 13,250 patients in the autoimmune-disease group, 145 experienced an SSNHL event (1.09%). Of the 66,250 in the control group, 484 experienced an SSNHL event (0.73%). The SSNHL risk was significantly higher in the autoimmune-disease group than in the control group. SSNHL incidence was significantly higher among patients with antiphospholipid syndrome (APS), multiple sclerosis (MS), rheumatoid arthritis (RA), and connective-tissue diseases including Sjögren syndrome and Behçet disease. In detailed stratified analyses using reinforced additional diagnostic codes, only RA patients had a significantly higher SSNHL incidence than the control group. CONCLUSION: The association of several autoimmune diseases with SSNHL was evaluated in this large-scale, population-based, big-data study. The risk of SSNHL was significantly higher in patients with APS, MS, RA, and connective-tissue diseases including Sjögren syndrome and Behçet disease than in patients without autoimmune diseases. SSNHL, in particular, was significantly associated with RA according to detailed analyses using reinforced additional diagnostic codes.

Corneal permeability changes in dry eye disease: an observational study.

BACKGROUND: Diagnostic tests for dry eye disease (DED), including ocular surface disease index (OSDI), tear breakup time (TBUT), corneal fluorescein staining, and lissamine staining, have great deal of variability. We investigated whether fluorophotometry correlated with previously established DED diagnostic tests and whether it could serve as a novel objective metric to evaluate DED. METHODS: Dry eye patients who have had established signs or symptoms for at least 6 months were included in this observational study. Normal subjects with no symptoms of dry eyes served as controls. Each eye had a baseline fluorescein scan prior to any fluorescein dye. Fluorescein dye was then placed into both eyes, rinsed with saline solution, and scanned at 5, 10, 15, and 30 min. Patients were administered the following diagnostic tests to correlate with fluorophotometry: OSDI, TBUT, fluorescein, and lissamine. Standard protocols were used. P < 0.05 was considered significant. RESULTS: Fifty eyes from 25 patients (DED = 22 eyes, 11 patients; Normal = 28 eyes, 14 patients) were included. Baseline scans of the dry eye and control groups did not show any statistical difference (p = 0.84). Fluorescein concentration of DED and normal patients showed statistical significance at all time intervals (p < 10(-5), 0.001, 0.002, 0.049 for 5, 10, 15, & 30 min respectively). Fluorophotometry values converged towards baseline as time elapsed, but both groups were still statistically different at 30 min (p < 0.01). We used four fluorophotometry scoring methods and correlated them with OSDI, TBUT, fluorescein, and lissamine along with adjusted and aggregate scores. The four scoring schemes did not show any significant correlations with the other tests, except for correlations seen with lissamine and 10 (p = 0.045, 0.034) and 15 min (p = 0.013, 0.012), and with aggregate scores and 15 min (p = 0.042, 0.017). CONCLUSIONS: Fluorophotometry generally did not correlate with any other DED tests, even though it showed capability of differentiating between DED and normal eyes up to 30 min after fluorescein dye instillation. There may be an aspect of DED that is missed in the current regimen of DED tests and only captured with fluorophotometry. Adding fluorophotometry may be useful in screening, diagnosing, and monitoring patients with DED.

Screening assay for small-molecule inhibitors of synaptojanin 1, a synaptic phosphoinositide phosphatase.

Elevation of amyloid ß-peptide (Aß) is critically associated with Alzheimer disease (AD) pathogenesis. Aß-induced synaptic abnormalities, including altered receptor trafficking and synapse loss, have been linked to cognitive deficits in AD. Recent work implicates a lipid critical for neuronal function, phosphatidylinositol-4,5-bisphosphate [PI(4,5)P2], in Aß-induced synaptic and behavioral impairments. Synaptojanin 1 (Synj1), a lipid phosphatase mediating the breakdown of PI(4,5)P2, has been shown to play a role in synaptic vesicle recycling and receptor trafficking in neurons. Heterozygous deletion of Synj1 protected neurons from Aß-induced synaptic loss and restored learning and memory in a mouse model of AD. Thus, inhibition of Synj1 may ameliorate Aß-associated impairments, suggesting Synj1 as a potential therapeutic target. To this end, we developed a screening assay for Synj1 based on detection of inorganic phosphate liberation from a water-soluble, short-chain PI(4,5)P2. The assay displayed saturable kinetics and detected Synj1's substrate preference for PI(4,5)P2 over PI(3,4,5)P3. The assay will enable identification of novel Synj1 inhibitors that have potential utility as chemical probes to dissect the cellular role of Synj1 as well as potential to prevent or reverse AD-associated synaptic abnormalities.

Emerging drugs for the treatment of dry eye disease.

INTRODUCTION: Dry eye disease (DED) is a common, age-related ocular condition that in its mildest forms causes bothersome symptoms of ocular discomfort, fatigue, and visual disturbance that interfere with quality of life and in its more severe forms causes chronic pain and fluctuating vision. Though it is highly prevalent and costs billions of dollars to manage, current treatments have largely been inadequate, making it a frustrating condition, both for physicians and patients alike. AREAS COVERED: This article will cover the recently discovered pathophysiology of DED that has prompted investigators to explore new molecules that target the core mechanisms that drive DED. These include anti-inflammatory/immune-modulatory drugs, secretagogues, lubricant, hormones, and autologous serum. Their potential mechanism of action and data from recent trials on efficacy/safety will be reviewed. EXPERT OPINION: The emerging drugs have a vast range of putative mechanisms of action that may not only provide symptomatic relief but may potentially break the vicious cycle of DED and provide long-lasting cure. Current and future research may change our perspective on DED and redefine its treatment algorithms.