Anti-MDA5 Antibody-Positive Clinically Amyopathic Dermatomyositis Associated With Multiple Heterologous Carcinomas: A Case Report.

Dermatomyositis (DM), an autoimmune disorder, is linked to increased malignancy risk. A 53-year-old man with anti-melanoma differentiation-associated gene 5 (MDA5)-positive clinically amyopathic dermatomyositis (CADM) and rapidly progressing interstitial lung disease (RP-ILD) developed heterochronous gastric and colorectal cancers. Early endoscopic screenings led to successful curative resections, preventing recurrence. Despite low cancer incidence assumptions in patients with anti-MDA5-positive RP-ILD, this case advocates for reevaluation and periodic cancer screenings to enhance management, considering the improved survival with intensive therapy. Vigilance for multiple carcinomas at various time points is vital in CADM management.

Clarithromycin-induced eosinophilic granulomatosis with polyangiitis: A case report.

A 75-year-old man presented to our hospital with chronic sinusitis, bronchiectasis, and chronic lower respiratory tract infections. He began taking erythromycin in August, X-2. The chronic lower respiratory tract infection gradually worsened, and clarithromycin was started on May 11, X. He became aware of fever and numbness in his lower legs on June 4, X. The sign occurred soon after oral clarithromycin and blood tests showed an elevated eosinophil count and C-reactive protein (CRP) levels, positive MPO-ANCA antibodies, and positive for drug-induced lymphocyte stimulation test (DLST); we diagnosed eosinophilic granulomatosis with polyangiitis (EGPA) associated with clarithromycin administration.

A case of thoracic SMARCA4-Deficient undifferentiated tumor successfully treated with combination Ipilimumab-Nivolumab.

Thoracic SMARCA4-deficient undifferentiated tumors are rare, with poor prognosis. A 73-year-old man presented to our hospital with dyspnea. Computed tomography-guided biopsy revealed a SMARCA4-deficient undifferentiated tumor. The patient was treated with combination ipilimumab-nivolumab. The tumor reduced in size after two courses.

Bronchoalveolar lavage fluid reveals factors contributing to the efficacy of PD-1 blockade in lung cancer.

Bronchoalveolar lavage is commonly performed to assess inflammation and identify responsible pathogens in lung diseases. Findings from bronchoalveolar lavage might be used to evaluate the immune profile of the lung tumor microenvironment (TME). To investigate whether bronchoalveolar lavage fluid (BALF) analysis can help identify patients with non-small cell lung cancer (NSCLC) who respond to immune checkpoint inhibitors (ICIs), BALF and blood were prospectively collected before initiating nivolumab. The secreted molecules, microbiome, and cellular profiles based on BALF and blood analysis of 12 patients were compared with regard to therapeutic effect. Compared with ICI nonresponders, responders showed significantly higher CXCL9 levels and a greater diversity of the lung microbiome profile in BALF, along with a greater frequency of the CD56+ subset in blood T cells, whereas no significant difference in PD-L1 expression was found in tumor cells. Antibiotic treatment in a preclinical lung cancer model significantly decreased CXCL9 in the lung TME, resulting in reduced sensitivity to anti-PD-1 antibody, which was reversed by CXCL9 induction in tumor cells. Thus, CXCL9 might be associated with the lung TME microbiome, and the balance of CXCL9 and lung TME microbiome could contribute to nivolumab sensitivity in patients with NSCLC. BALF analysis can help predict the efficacy of ICIs when performed along with currently approved examinations.

Balance of Drug Residence and Diffusion in Lacrimal Fluid Determine Ocular Bioavailability in In Situ Gels Incorporating Tranilast Nanoparticles.

We previously designed ophthalmic formulations (nTRA) containing tranilast nanoparticles (Tra-NPs) with high uptake into ocular tissues. In this study, we used in situ gel (ISG) bases comprising combinations of pluronic F127 (F127) and methylcellulose (MC/F127), pluronic F68 (F68/F127), and Carbopol (Car/F127), and we developed in situ gels incorporating Tra-NPs (Tra-NP-incorporated ISNGs) such as nTRA-F127, nTRA-MC/F127, nTRA-F68/F127, and nTRA-Car/F127. Moreover, we demonstrated the therapeutic effect on conjunctival inflammation using lipopolysaccharide-induced rats. Each Tra-NP-incorporated ISNG was prepared by the bead mill method, the particle size was 40-190 nm, and the tranilast release and diffusion from formulation were nTRA > nTRA-F127 > nTRA-F68/F127 > nTRA-Car/F127 > nTRA-MC/F127. In the Tra-NP-incorporated ISNGs, the tranilast residence time in the lacrimal fluid, cornea, and conjunctiva was prolonged, although the Cmax was attenuated in comparison with nTRA. On the other hand, no significant difference in conjunctival inflammation between non- and nTRA-F127-instilled rats was found; however, the nTRA-F68/F127, nTRA-Car/F127, and nTRA-MC/F127 (combination-ISG) attenuated the vessel leakage, nitric oxide, and tumor necrosis factor-α expression. In particular, nTRA-F68/F127 was significant in preventing the conjunctival inflammation. In conclusion, we found that the combination-ISG base prolonged the residence time of Tra-NPs; however, Tra-NP release from the formulation was attenuated, and the Tmax was delayed longer than that in nTRA. The balance of drug residence and diffusion in lacrimal fluid may be important in providing high ocular bioavailability in formulations containing solid nanoparticles.

Comprehensive assessment of PD-L1 expression, tumor mutational burden and oncogenic driver alterations in non-small cell lung cancer patients treated with immune checkpoint inhibitors.

OBJECTIVES: Immune checkpoint inhibitors (ICIs) have proven to be effective treatment for lung cancer. However, a precise predictive immuno-oncology biomarker is still under development. We investigated the associations among PD-L1 expression, tumor mutational burden (TMB), and oncogenic driver alterations in advanced non-small cell lung cancer (NSCLC) patients treated with ICIs. MATERIALS AND METHODS: This multicenter cohort study included 1017 lung cancer patients. PD-L1 expression using four IHC assays (22C3, 28-8, SP263, SP142), TMB by whole-exome sequencing and oncogenic driver alterations were analyzed comprehensively. Clinical characteristics, treatment and survival data were collected. RESULTS: The results of 22C3 and 28-8 for PD-L1 expression showed acceptable concordance (k = 0.89; 95% confidence interval [CI], 0.87-0.92), and the clinical outcomes of ICIs classified according to PD-L1 expression by both assays were also approximately the same. There was slight concordance (k = 0.16; 95% CI, 0.11-0.22) between 22C3 and SP142, and high PD-L1 expression by SP142 was correspond to very high PD-L1 expressions by other assays. Patients with both high PD-L1 expression and high TMB showed a good response to ICIs with the response rate of 64% and median progression-free survival of 9.0 months despite of small population. Common EGFR or STK11 mutations showed a lower rate of high PD-L1 expression and a worse efficacy of ICIs and KRAS mutations had no negative impact on response to ICIs. CONCLUSION: Comprehensive assessment of PD-L1 expression, TMB, and oncogenic driver alterations would help to better predict the clinical outcomes of ICIs in NSCLC patients.

The ratio of T790M to EGFR-activating mutation predicts response of osimertinib in 1st or 2nd generation EGFR-TKI-refractory NSCLC.

The most frequent mechanism of resistance after 1st/2nd-generation (G) epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) is secondary point mutation Thr790Met (T790M) in EGFR. Afatinib followed by osimertinib (Afa group) may provide better outcomes for T790M-positive non-small cell lung cancer (NSCLC) than 1st-G EGFR-TKI followed by osimertinib (1st-G group). We studied 111 consecutive NSCLC patients with T790M mutation treated with osimertinib after progression following 1st/2nd-G EGFR-TKI between March 28, 2016 and March 31, 2018. We analyzed the ratio of T790M to EGFR-activating mutation (T790M ratio) in post EGFR-TKI resistance re-biopsy tissue using droplet digital polymerase chain reaction. And investigated whether afatinib purified the T790M mutation more than 1st-G EGFR-TKI. Among 60 patients with preserved re-biopsy tissue, we analyzed 38 having adequate DNA content. The response rate in Afa group was 81.8% (n = 11) and 1st-G group was 85.2% (n = 27). The mean T790M ratio in total population was 0.3643. The ratio in those with response to osimertinib was significantly higher than in the non-responders (0.395, 0.202; p = 0.0231) and was similar in Afa and 1st-G group (0.371, 0.362; p = 0.9693). T790M ratio significantly correlated with osimertinib response and was similar between the 1st/2nd-G EGFR-TKIs in 1st/2nd-G EGFR-TKI-refractory tumors.

Exacerbation of liver dysfunction in non-alcoholic steatohepatitis patients during the coronavirus disease 2019 (COVID-19) pandemic.

Many people were forced to stay at home, including non-alcoholic steatohepatitis (NASH) patients, however it is unclear how this home-life has affected the prognosis of NASH. In this study, we examined the influences of living at home during the coronavirus disease 2019 (COVID-19) pandemic NASH patients. In this study, we compared the clinical parameters of NASH patients without COVID-19 infection 3 months before with those 3 months after the declaration of a state of emergency. In the results, the changes of aspartate transaminase and alanine aminotransferase in the 3 months before (aspartate transaminase, -3.6 ± 13.8 U/L; alanine aminotransferase, -6.8 ± 19.5 U/L) was significantly exacerbated in the 3 months after (aspartate transaminase, 2.3 ± 7.5 U/L; alanine aminotransferase, 1.7 ± 10.4 U/L). Furthermore, the changes of the fibrosis-4 index in the 3 months before (-0.27 ± 0.84) was also significantly exacerbated in the 3 months after (0.38 ± 0.96). In conclusion, liver dysfunctions in NASH patients were exacerbated due to the emergency declaration and outing restriction which accompanied COVID-19.

Hepatic F4/80+ CD11b+ CD68- cells influence the antibacterial response in irradiated mice with sepsis by Enterococcus faecalis.

Gut-associated sepsis is a major problem in patients undergoing abdominal radiation therapy; the majority of pathogens causing this type of sepsis are translocated from the gut microbiota. While treating sepsis, bacterial clearance must be achieved to ensure patient survival, and the hepatic immune response is responsible for this process. In particular, Kupffer cells play a crucial role in the hepatic immune response against infectious agents. Recently, two populations of Kupffer cells have been described: liver-resident macrophages (Mϕ) (F4/80+ CD11b- CD68+ cells) and hepatic Mϕ derived from circulating monocytes (F4/80+ CD11b+ CD68- cells). We examined the properties of both types of hepatic Mϕ obtained from irradiated and normal mice and their role in sepsis. Hepatic F4/80+ CD11b- CD68+ cells from both normal and irradiated mice did not show any antibacterial activity. However, F4/80+ CD11b+ CD68- cells from normal mice behaved as effector cells against sepsis by Enterococcus faecalis, although those from irradiated mice lost this ability. Moreover, hepatic F4/80+ CD11b+ CD68- cells from normal infected mice were shown to be IL-12+ IL-10- CD206- CCL1- (considered M1Mϕ), and hepatic F4/80+ CD11b- CD68+ cells from the same mice were shown to be IL-12- IL-10+ CD206+ CCL1- (considered M2aMϕ). When normal mice were exposed to radiation, hepatic F4/80+ CD11b+ CD68- cells altered their phenotype to IL-12- IL-10+ CD206- CCL1+ (considered M2bMϕ), independent of infection, but hepatic F4/80+ CD11b- CD68+ cells remained IL-12- IL-10+ CD206+ CCL1- (M2aMϕ). In addition, hepatic F4/80+ CD11b+ CD68- cells from irradiated mice acquired antibacterial activity upon treatment with CCL1 antisense oligodeoxynucleotides. Therefore, the characteristics of hepatic F4/80+ CD11b+ CD68- cells play a key role in the antibacterial response against gut-associated sepsis.

Extracellular Water-to-total Body Water Ratio as an Objective Biomarker for Frailty in Lung Cancer Patients.

BACKGROUND/AIM: Our previous study revealed the association between extracellular water-to-total body water ratio (ECW/TBW) and the therapeutic durability of chemotherapy and/or immune checkpoint inhibitors in advanced lung cancer. We retrospectively examined the usefulness of ECW/TBW in detecting frailty compared to other bioelectrical impedance (BIA) parameters in a larger number of patients. PATIENTS AND METHODS: Lung cancer patients underwent BIA before anti-cancer therapy at our hospital between June 1, 2018 and July 31, 2020. RESULTS: Of 99 patients, 26 were assigned to ECW/TBW≥0.4 (higher group: HG) and 57 to ECW/TBW<0.4 (lower group: LG). ECW/TBW increased significantly with performance deterioration and ageing. HG patients had significantly shorter time-to-treatment failure (TTF) than LG patients. In patients with performance status 0-1, those in the HG had shorter TTF than those in the LG. ECW/TBW was the only independent predictor of TTF according to multivariate analysis. CONCLUSION: ECW/TBW is an objective biomarker for detecting frailty among lung cancer patients.

Phase 2 study of bevacizumab plus carboplatin/nab-paclitaxel followed by bevacizumab plus nab-paclitaxel for non-squamous non-small cell lung cancer with malignant pleural effusion.

Objectives Vascular endothelial growth factor plays an important role in the pathogenesis of malignant pleural effusion (MPE). We previously showed the efficacy of bevacizumab (Bev) plus carboplatin (CBDCA)/paclitaxel (PTX) in the treatment of non-small lung cell cancer (NSCLC) with MPE. However, the toxicities were a little severe, and the efficacy was not satisfied sufficiently. Therefore, we conducted a phase II study for NSCLC with MPE to evaluate the efficacy and safety of Bev plus CBDCA/nab-PTX, which is a new combination therapy. Methods Chemotherapy-naive non-squamous (SQ) NSCLC patients with MPE participated in the study. A single aspiration (not allowing chest tube drainage) was allowed before chemotherapy. Patients received a maximum of six cycles of Bev (15 mg/kg, day1) plus CBDCA (AUC 6, day1)/nab-PTX (100 mg/m2, day1, 8) every 3 weeks followed by Bev (15 mg/kg, day1) plus nab-PTX (100 mg/m2, day1, 8) every 3 weeks without disease progression or unacceptable severe toxicities. The primary endpoint was objective response rate (ORR). Results The study enrollment was ceased because of suspension of the registration period (as scheduled) after 12 of 20 planned patients were treated successfully between March 2014 and February 2018. The ORR was 58.3 % (95 % CI, 27.7-84.8 %), and the disease control rate was 100 % (95 % CI, 73.5-100 %). Eight patients received maintenance therapy. Median progression-free and overall survival times were 14.4 and 26.9 months, respectively. Most patients experienced hematological toxicities, including ≥ grade 3 neutropenia and anemia; none experienced severe bleeding events and grade 5 toxicities. Conclusion The combination of Bev plus CBDCA/nab-PTX, a novel combination, might have efficacy with acceptable toxicities in chemotherapy-naïve non-SQ NSCLC patients with MPE.Trial Registration University Hospital Medical Information Network in Japan (UMIN) Clinical Trials Registry (No. UMIN000013329) registered on 4th March 2014.

Transbronchial Cryobiopsy for Miliary Tuberculosis Mimicking Hypersensitivity Pneumonitis.

Miliary tuberculosis is a potentially lethal type of tuberculosis that results from the hematogenous dissemination of Mycobacterium tuberculosis bacilli. We herein describe the case of a 34-year-old man that presented with a one-month history of cough and fever, while his sputum smear results were negative. Chest computed tomography revealed bilateral centrilobular ground-glass opacification (GGO), suggestive of hypersensitivity pneumonitis; thus, bronchoscopy was performed. Cryobiopsy specimens revealed necrotic granulomas. A re-examination of sputum after bronchoscopy identified Mycobacterium tuberculosis, and miliary tuberculosis was diagnosed. A cryobiopsy might be useful for diagnosing miliary tuberculosis pathologically, particularly when miliary nodules may be masked by GGO.

Significance of Pre-treatment Interferon-gamma Release in Patients With Non-small-cell Lung Cancer Receiving Immune Checkpoint Inhibitors.

BACKGROUND/AIM: We retrospectively investigated the significance of pre-treatment interferon-gamma release (IGR) as a biomarker for predicting the efficacy of immune checkpoint inhibitor treatment (ICI-tx). PATIENTS AND METHODS: This study included non-small-cell lung cancer patients who received ICI-tx between January 1, 2016 and April 30, 2019. IGR was measured using the positive control of an enzyme-linked immunosorbent assay. We defined the pre-treatment cut-off level of IGR as 10 IU/ml. RESULTS: Fifty-four patients were divided into two groups; those with an IGR ≤10 IU/ml (lower group: LG) (n=15) and those with >10 IU/ml (higher group: HG) (n=39). The time to treatment failure (TTF) in the HG was significantly longer than that in the LG. In multivariate analyses, C-reactive protein and IGR levels were significant risk factors for TTF. CONCLUSION: Pre-treatment IGR level of >10 IU/ml is recommended to identify those patients who will respond favourably to ICI-tx.

In Situ Gelling Systems Using Pluronic F127 Enhance Corneal Permeability of Indomethacin Nanocrystals.

We previously designed an ophthalmic dispersion containing indomethacin nanocrystals (IMC-NCs), showing that multiple energy-dependent endocytoses led to the enhanced absorption of drugs from ocular dosage forms. In this study, we attempted to prepare Pluronic F-127 (PLF-127)-based in situ gel (ISG) incorporating IMC-NCs, and we investigated whether the instillation of the newly developed ISG incorporating IMC-NCs prolonged the precorneal resident time of the drug and improved ocular bioavailability. The IMC-NC-incorporating ISG was prepared using the bead-mill method and PLF-127, which yielded a mean particle size of 50-150 nm. The viscosity of the IMC-NC-incorporating ISG was higher at 37 °C than at 10 °C, and the diffusion and release of IMC-NCs in the IMC-NC-incorporating ISG were decreased by PLF-127 at 37 °C. In experiments using rabbits, the retention time of IMC levels in the lacrimal fluid was enhanced with PLF-127 in the IMC-NC-incorporating ISG, whereby the IMC-NC-incorporating ISG with 5% and 10% PLF-127 increased the transcorneal penetration of the IMCs. In contrast to the results with optimal PLF-127 (5% and 10%), excessive PLF-127 (15%) decreased the uptake of IMC-NCs after instillation. In conclusion, we found that IMC-NC-incorporating ISG with an optimal amount of PLF-127 (5-10%) resulted in higher IMC corneal permeation after instillation than that with excessive PLF-127, probably because of the balance between higher residence time and faster diffusion of IMC-NCs on the ocular surface. These findings provide significant information for developing ophthalmic nanomedicines.

Liver dysfunction is associated with poor prognosis in patients after immune checkpoint inhibitor therapy.

Immune-related adverse events (irAEs) are induced by immune checkpoint inhibitors (ICIs). Liver is one of the main target organs which irAEs occur and we investigated the influence of liver dysfunction on prognosis of patients after ICIs. From July 2014 to December 2018, 188 patients with diverse cancers who received ICIs (nivolumab or pembrolizumab) were enrolled. Twenty-nine patients experienced liver dysfunction of any grades after ICIs. Progression-free survival (PFS) was significantly shorter in the liver dysfunction-positive group than in the liver dysfunction-negative group, and a similar result was obtained for Overall survival (OS). Multiple logistic regression analysis revealed liver metastasis and alanine aminotransferase before ICIs were associated with a higher incidence of liver dysfunction after ICIs. Regardless of liver metastasis, PFS and OS were significantly shorter in the liver dysfunction-positive group. In conclusion, this study suggests liver dysfunction is associated with poor prognosis in patients after ICIs with diverse cancers.

The Association Between Extracellular Water-to-Total Body Water Ratio and Therapeutic Durability for Advanced Lung Cancer.

BACKGROUND/AIM: Extracellular water-to-total body water ratio (ECW/TBW) measured by bioelectrical impedance analysis (BIA) reportedly predicts clinical outcomes of various diseases. The aim of this retrospective study was to examine the association between ECW/TBW and therapeutic durability of chemotherapy and/or immune checkpoint inhibitors in advanced lung cancer. PATIENTS AND METHODS: Patients with advanced lung cancer underwent BIA before chemotherapy and/or treatment with immune checkpoint inhibitors at our hospital between June 2018 and November 2019. RESULTS: Of 75 patients, 18 with ECW/TBW ≥0.4 were assigned to the overhydrated group (OH-G) and 57 patients ECW/TBW <0.4 were assigned to the non-overhydrated group (NOH-G). The median time-to-treatment failure was significantly shorter in the OH-G than in the NOH-G (p=0.003). Multivariate analysis revealed that ECW/TBW ≥0.4 predicted treatment failure [hazard ratio (HR)=2.508, 95% confidence interval (CI)=1.19-5.27; p=0.01]. CONCLUSION: The ECW/TBW may be an objective parameter for predicting therapeutic durability in advanced lung cancer.

Safety and efficacy of afatinib for the treatment of non-small-cell lung cancer following osimertinib-induced interstitial lung disease: A retrospective study.

Background Osimertinib is one of the first-line treatments for advanced non-small-cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations. However, the occurrence rate of osimertinib-induced interstitial lung disease (ILD) is particularly high in Japanese patients and little information on subsequent cancer treatment options after recovery from osimertinib-induced ILD is currently available. Thus, this study aims to determine the safety and efficacy of afatinib for the treatment of NSCLC following osimertinib-induced ILD. Methods We retrospectively investigated the clinical courses of all NSCLC patients with EGFR mutations at our facility between August 2018 and September 2019, who received osimertinib as first-line treatment and were subsequently treated with afatinib after developing osimertinib-induced ILD. Results Forty-two patients received osimertinib treatment at our facility during the study period, and four patients received afatinib after developing osimertinib-induced ILD. All events of ILD improved either spontaneously or with steroid therapy before the initiation of afatinib. For the four patients who were retrospectively reviewed, the overall response rate to afatinib therapy was 75%, and the disease control rate was 100%. During the study period, no ILD recurrence was observed in any of the four patients. Conclusions According to our study findings, afatinib treatment after osimertinib-induced ILD is considered safe and effective and it can be used as one of the treatment options for NSCLC following osimertinib-induced ILD.

Significance of Quantitative Interferon-gamma Levels in Non-small-cell Lung Cancer Patients' Response to Immune Checkpoint Inhibitors.

BACKGROUND/AIM: We aimed to study the association between the quantitative interferon-gamma (IFN-γ) levels and clinical outcomes in non-small-cell lung cancer (NSCLC) patients receiving immune checkpoint inhibitors (ICIs). PATIENTS AND METHODS: Sample collection for IFN-γ release assay (IGRA) was performed within 14 days before treatment (T1), on day 22±7 (T3), and on day 43±7 (T4). The stored specimens over 10 IU/ml in IGRA were re-examined using the dilution method (with saline as the dilution medium). The patients were classified into Lower and Higher groups by 7.06 IU/ml as a cut-off of IFN-γ levels at T1. RESULTS: Median progression-free survival in the Higher group was significantly longer than that in the Lower group. IFN-γ levels in the non-progression disease group were significantly higher than those in the progression disease group. IFN-γ levels at T1 in patients with immune-related adverse events were significantly lower compared to those at T3. CONCLUSION: IFN-γ could be a biomarker for NSCLC patients receiving ICIs.

Development of Severe Heart Failure in a Patient with Squamous Non-small-cell Lung Cancer During Nivolumab Treatment.

Cardiac side effects associated with immune checkpoint inhibitors (ICIs) are an uncommon but serious complication with a relatively high mortality. We experienced a case of cardiomyopathy induced by nivolumab. Echocardiography showed diffuse hypo-kinesis of the left ventricular cardiac wall and a significant decrease in the ejection fraction, like dilated cardiomyopathy. The myocardial biopsy showed non-inflammatory change; cardiac function gradually improved after treatment of acute heart failure without a corticosteroid. Although non-inflammatory left ventricular dysfunction induced by ICIs is rare, it is a reported cardiovascular toxicity. Physicians should consider this complication when treating patients with ICIs for malignant diseases.

Novel Sustained-Release Drug Delivery System for Dry Eye Therapy by Rebamipide Nanoparticles.

The commercially available rebamipide ophthalmic suspension (CA-REB) was approved for clinical use in patients with dry eye; however, the residence time on the ocular surface for the traditional formulations is short, since the drug is removed from the ocular surface through the nasolacrimal duct. In this study, we designed a novel sustained-release drug delivery system (DDS) for dry eye therapy by rebamipide nanoparticles. The rebamipide solid nanoparticle-based ophthalmic formulation (REB-NPs) was prepared by a bead mill using additives (2-hydroxypropyl-ß-cyclodextrin and methylcellulose) and a gel base (carbopol). The rebamipide particles formed are ellipsoid, with a particle size in the range of 40-200 nm. The rebamipide in the REB-NPs applied to eyelids was delivered into the lacrimal fluid through the meibomian glands, and sustained drug release was observed in comparison with CA-REB. Moreover, the REB-NPs increased the mucin levels in the lacrimal fluid and healed tear film breakup levels in an N-acetylcysteine-treated rabbit model. The information about this novel DDS route and creation of a nano-formulation can be used to design further studies aimed at therapy for dry eye.