Intravitreal Methotrexate Injections Research Articles

Serial Intravitreal Methotrexate Injections to Combat Recurrent Proliferative Vitreoretinopathy in a Pediatric Patient

Purpose: To describe the use of serial intravitreal methotrexate to combat proliferative vitreoretinopathy (PVR) in a pediatric patient with recurrent retinal detachment (RD). Methods: A retrospective case analysis was performed. Results: A 6-year-old patient with bilateral panuveitis presented with recurrent RD in the right eye. After treatment with 2 RD surgeries performed elsewhere, the patient developed PVR that necessitated 5 additional surgeries for recurrent detachment. The patient subsequently received a total of 8 injections of methotrexate 400 µg/0.1 mL (0.1 mL) in the operating room at 1- to 2-week intervals over a 3-month period. Through 13 months of follow-up after the first methotrexate injection, there was no evidence of recurrent RD, PVR, or epiretinal membrane formation. Conclusions: Frequent serial intravitreal methotrexate injections apparently played a role in preventing recurrent PVR formation in this pediatric patient with a history of intraocular inflammation and recurrent RD.

Occlusive retinal vasculitis as a presenting feature of primary vitreoretinal lymphoma relapse.

To report a case of primary vitreoretinal lymphoma (PVRL) relapse presenting as occlusive retinal vasculitis with secondary neovascularization. A retrospective case report. A Forty-year-old woman presented to the clinic with complaints of blurring of vision in the left eye for 4 months. Her best corrected visual acuity (BCVA) was 20/20 and 20/500 in the right and left eye, respectively. Both eyes' vitreous cavities showed vitreous opacities (2+). Both eyes fundus showed multifocal yellowish-white subretinal infiltration. A diagnostic vitreous and subretinal biopsy of the left eye revealed large lymphoid cells with CD20 positivity, confirming the diagnosis of PVRL. The patient received twelve intravitreal methotrexate (MTX) injections in both eyes over a course of 2 months, following which the lesions completely resolved. However, after 5 months, the left eye showed characteristic subretinal lesions along with perivascular exudates and retinal haemorrhages, diagnosed as PVRL relapse presenting as occlusive retinal vasculitis. Fluorescein angiography revealed retinal neovascularization (NVE), for which pan-retinal photocoagulation was performed along with repeated intravitreal MTX injection. PVRL is a great masquerader, and although rare, PVRL relapse can present as occlusive retinal vasculitis with secondary NVE, thereby delaying diagnosis and subsequent treatment.

Intravitreal injection of methotrexate in persistent diabetic macular edema: a 6-month study.

Diabetic macular edema (DME) affects approximately 10% of patients with diabetes mellitus. This condition can cause blurred or distorted vision, which significantly affects the quality of life of these patients. We evaluated the therapeutic effects of intravitreal methotrexate (MTX) injections on persistent DME. This prospective interventional case series included patients with confirmed persistent DME that was unresponsive to previous standard treatments. The patients underwent comprehensive eye examinations and macular imaging with optical coherence tomography (OCT). A single intravitreal MTX injection (400 µg MTX in 0.16 mL solution) was administered, followed by patient assessments at 1, 3, and 6 months after injection. Best-corrected distance visual acuity (BCDVA), intraocular pressure (IOP), macular thickness (MT), and central subfield thickness (CST) were measured at baseline and post-injection to evaluate treatment efficacy. We included 33 eyes of 30 patients with a mean (standard deviation [SD], range) age of 62.7 (8.3, 44 to 77) years, of whom 17 (56.7%) were men and 13 (43.3%) were women. All participants had type 2 diabetes mellitus, with a mean (SD, range) duration of 17.0 (6.8, 10 to 31) years. Most participants (n = 27 eyes, 81.8%) had non-proliferative diabetic retinopathy, and six eyes (18.2%) had regressed proliferative diabetic retinopathy. Four eyes (12.1%) had undergone prior macular laser photocoagulation. The mean (SD) number of prior intravitreal bevacizumab injections was 3.4 (0.8), and 29 eyes (87.8%) had received one intravitreal triamcinolone injection. During the study period, a statistically significant difference was observed in CST (P < 0.05); however, no statistically significant differences were observed in BCDVA, MT, or IOP (P > 0.05). Pairwise comparison revealed a significant decrease in CST at 6 months post-injection compared to the baseline value (P < 0.05). During the investigation period, no side effects of MTX, such as macular edema, retinal tears, vitreous hemorrhage, endophthalmitis, or vision loss, were observed. A single intravitreal MTX injection significantly reduced CST in patients with persistent DME, without relevant safety concerns. However, no significant improvement in functional outcomes was observed. Therefore, there is no strong evidence to recommend its use as a treatment for pDME. Further studies, preferably randomized clinical trials with long-term follow-ups, are warranted to assess the long-term efficacy, safety, and potential benefits of intravitreal MTX for the treatment of persistent DME.

Clinical factors for central nervous system progression and survival in primary vitreoretinal lymphoma.

Primary vitreoretinal lymphoma (PVRL) is a rare subtype of malignant lymphoma with a poor prognosis because of high frequency of central nervous system (CNS) progression. Identification of factors associated with CNS progression is essential to improve the prognosis of patients with PVRL. We conducted a retrospective study of 54 patients diagnosed with PVRL and treated at our hospital to identify factors associated with CNS progression and prognosis. All patients were treated with intravitreal methotrexate (MTX) injections in the affected eyes until lesion resolution. Twenty-four patients were treated with systemic administration of high-dose MTX (systemic HD-MTX) every other week for a total of five cycles following intravitreal MTX injection. Of 24 patients, 20 completed five cycles of systemic HD-MTX. The 5-year cumulative incidence of CNS progression and overall survival (OS) rate were 78.0% and 69.0% respectively. By univariate and multivariate analyses, bilateral disease and the detection of B-cell clonality confirmed by flow cytometric analysis were risk factors associated with CNS progression. Moreover, systemic HD-MTX completion reduced the risk of CNS progression and was identified as a factor affecting OS. In this study, factors for CNS progression identified may potentially contribute to the optimized therapeutic stratification to improve the survival of patients with PVRL.

Role of Intrasilicon Oil Methotrexate Injection to Prevent Development of Proliferative Vitreoretinopathy

Purpose: To determine the role of intra-silicon oil methotrexate injection to prevent Proliferative Vitreoretinopathy. Study Design: Quasi experimental Study. Place and Duration: Ophthalmology department of Sahiwal Teaching Hospital, Sahiwal from February 2022 to August 2022. Methods: Study included patients of either gender, older than 19 years with rhegmatogenous retinal detachment with Proliferative vitreoretinopathy (PVR) grade B or less. There were two groups and each group had fifty-one patients. All patients underwent pars plana vitrectomy and silicon oil tamponade. Group 1 was control group. Group 2 had intravitreal injections of methotrexate 500mg at the end of surgery. We repeated the injections at 1st, 2nd, and 4th week postoperatively. Results: There were 56 (54.9%) male and 46 (45.1%) female patients. Postoperatively visual acuity improved in thirty cases (58.82%) in group 1 and in forty-two cases (82.35%) in group 2. Postoperatively PVR developed in 11 (21.57%) patients in group 1 while in group 2 no patient had PVR. Recurrent Retinal detachment occurred in 9 (19.61%) patients in group 1 and 3 (5.88%) patients in group 2. Chi square test demonstrated statistically significant difference in the frequency of development of PVR and re-detachment of retina between two groups, p&lt;0.05. Conclusion: Methotrexate is an effective adjuvant used in Pars plana Vitrectomy for rhegmatogenous retinal detachment repair. It prevents Proliferative vitreoretinopathy resulting in better surgical and functional outcome.

Effect of Oral Riboflavin and Direct-sun UV-A on Tumor Necrosis Factor Alpha (TNF-α) Concentrations in Tears of Mild-Moderate Keratoconus Patients

Purpose: To determine the role of intra-silicon oil methotrexate injection to prevent Proliferative Vitreoretinopathy. Study Design: Quasi experimental Study. Place and Duration: Ophthalmology department of Sahiwal Teaching Hospital, Sahiwal from February 2022 to August 2022. Methods: Study included patients of either gender, older than 19 years with rhegmatogenous retinal detachment with Proliferative vitreoretinopathy (PVR) grade B or less. There were two groups and each group had fifty-one patients. All patients underwent pars plana vitrectomy and silicon oil tamponade. Group 1 was control group. Group 2 had intravitreal injections of methotrexate 500mg at the end of surgery. We repeated the injections at 1st, 2nd, and 4th week postoperatively. Results: There were 56 (54.9%) male and 46 (45.1%) female patients. Postoperatively visual acuity improved in thirty cases (58.82%) in group 1 and in forty-two cases (82.35%) in group 2. Postoperatively PVR developed in 11 (21.57%) patients in group 1 while in group 2 no patient had PVR. Recurrent Retinal detachment occurred in 9 (19.61%) patients in group 1 and 3 (5.88%) patients in group 2. Chi square test demonstrated statistically significant difference in the frequency of development of PVR and re-detachment of retina between two groups, p&lt;0.05. Conclusion: Methotrexate is an effective adjuvant used in Pars plana Vitrectomy for rhegmatogenous retinal detachment repair. It prevents Proliferative vitreoretinopathy resulting in better surgical and functional outcome.

Efficacy and Safety of BTK Inhibitors in Vitreoretinal Lymphoma: A Single-Center, Retrospective Analysis of 24 Patients

Background: Vitreoretinal lymphoma (VRL) is a special subtype of rare central nervous system lymphoma (PCNSL). Most of the pathologic types are diffuse large B-cell lymphoma of non-germinal central origin. Currently, the optimal treatment strategy for VRL is not clear, and the traditional treatment usually includes about 20 repeated intravitreal injections of low doses of methotrexate or intraocular local radiotherapy. Eventually, however, 60-90% of VRL will progress to PCNSL. Therefore, CNS prophylaxis of VRL patients is very important. A previous prospective clinical study of our research group (including 10 VRL patients) confirmed that single-drug BTK inhibitors can replace repeated intravitreal injection of low doses of methotrexate, with rapid effect, high safety, and certain value in preventing CNS progression. Methods: In order to further clarify the efficacy and safety of BTK inhibitors in VRL patients, we included 24 VRL patients who were consecutively admitted to the Hematology Department of Beijing Tongren Hospital from May 2020 to December 2022, and retrospectively analyzed their clinical features, treatment methods, treatment outcomes, survival status and treatment-related adverse reactions. Results: Of the 24 patients, 14 were female and 10 were male, with a median age of 62 years old (36-75). There were 18 patients with primary VRL (PVRL) and 6 patients with secondary VRL (SVRL) to PCNSL. The IL-10 in aqueous humor/vitreous fluid at baseline was significantly increased in all patients (362.1±89.5pg/mL), and the IL-10/IL-6 ratio was greater than 1. Except for one patient with both uncontrolled PCNSL and VRL, the other 23 VRL patients showed no evidence of CNS involvement by brain MRI and cerebrospinal fluid detection. All 24 patients were treated with a BTK inhibitor (Zanubrutinib 160mg bid, or Orelabrutinib 150mg qd), of whom, 9 VRL patients were also treated with intravitreal methotrexate injection (0.4mg/ time, weekly ×12 times → monthly ×9 times) concurrently, and the remaining 15 patients did not receive any antitumor therapy other than BTK inhibitors. After 1 month of treatment with BTK inhibitors, the efficacy was evaluated by slit lamp microscope, optical coherence tomography (OCT), and aqueous humor cytokines. 21 patients achieved CR (87.5%), 2 PR (8.3%), and 1 PD (progression of CNS lesion but improvement of intraocular disease). The IL-10/IL-6 levels in aqueous humor were lower than 1 in all 24 patients 1 month after treatment, and the IL-10 levels in aqueous humor were slightly higher than the normal range in two patients. The median duration of BTK inhibitors use was 10 months (1.5-23.0 months). At a median follow-up of 17 months (5.4-31.5 months), 15 patients (62.5%) developed disease progression, including 11 patients (45.8%) with CNS progression and 4 patients (16.7%) with intraocular recurrence. The median progression-free survival (PFS) time was 11.9 months, and the median overall survival (OS) time was not reached. The 1-year and 2-year PFS rates were 34% and 26%, and the 1-year and 2-year OS rates were 96% and 82%, respectively. The recurrence rate was 33.3% in the combined treatment group and 80.0% in the BTK inhibitors monotherapy group. A total of three patients died, all due to CNS progression. BTK inhibitors were generally well tolerated in VRL patients, with no adverse reactions that led to treatment discontinuation. 4 patients had grade 1-2 hypertension (16.7%), 1 patient had grade 1 hypotension (4.2%), 2 patients had grade 1 joint pain (8.5%), and 6 patients had grade 1 subcutaneous hemorrhage and ecchymosis (25.0%). Four patients developed COVID-19 infection while taking the drug and the drug was suspended. All four patients recovered from COVID-19 infection within 2 weeks and did not develop significant pneumonia. Conclusion: This is the largest report regarding the use of BTK inhibitors in VRL patients. BTK inhibitor has a rapid local control effect on VRL and is well tolerated. However, BTK inhibitors monotherapy has unsatisfied preventive effect on the CNS, and it is still necessary to explore the value of combinational therapy, such as combined BTK inhibitors and high-dose methotrexate.

Regression of Primary Vitreoretinal Lymphoma (Pvrl) And Perivascular Flower Bud Like Lesions (Pfbls) on Octa After Intravitreal Methotrexate Injection Series

Primary Vitreoretinal Lymphoma (PVRL) is a rare and aggressive type of intraocular lymphoma that affects the eye. PVRL is most commonly diagnosed in individuals in their sixth to eighth decade of life, but it can occur in younger, immunocompromised individuals. PVRL is challenging to diagnose due to its non-specific presentations, and a delay in diagnosis from the onset of symptoms can exceed 12 months. CNS involvement in PVRL is common, and patients may develop CNS involvement within a mean interval of 8-29 months after diagnosis. We present a case of a 73-year-old man who presented to the emergency department with gradual decline in vision in his left eye over the past two years, with acute worsening over the past two weeks. The patient was diagnosed with PVRL with CNS involvement based on exam, imaging and biopsy findings. The patient received intravitreal injection of methotrexate in the left eye and systemic treatment with rituximab and ibrutinib. The patient’s visual acuity improved in the left eye, and regression of tumor size was noted on the fundus exam, OPTOS, and OCTA. Prompt referral to a medical center and early diagnosis are essential in managing PVRL to prevent potential vision loss. Various imaging modalities such as fluorescein angiography, optical coherence tomography, and optical coherence tomography angiography can be helpful in diagnosis and management of PVRL. However, the use of optical coherence tomography angiography has been only described in few case studies. The management of PVRL remains a challenge, with limited treatment options available, including systemic chemotherapy and/or radiation therapy

Vitreoretinal Involvement by Indolent T-cell Lymphoproliferative Disorder of the Gastrointestinal Tract Diagnosed by Fluorescence In Situ Hybridization.

To describe an exceedingly rare presentation of secondary vitreoretinal involvement by the uncommon entity "indolent T-cell lymphoproliferative disorder of the gastrointestinal tract" and illustrate the utility of fluorescence in situ hybridization for diagnosis. Case report. 57-year-old female. A 57-year-old female with presumed iritis on chronic topical prednisolone acetate presented with increased vitreous opacities in the right eye. She had a history of biopsy-confirmed indolent T-cell lymphoproliferative disorder (iTLPD-GI) involving the stomach and duodenum, JAK2-rearrangment-positive, controlled on maintenance oral methotrexate. Vitreous biopsy was unremarkable with small CD3 and CD4-positive, CD-20 negative lymphocytes, along with histiocytes and fibroblasts. Immunostains showed CD4 positivity, and fluorescence in situ hybridization revealed a JAK2 gene rearrangement, consistent with the patient's previously diagnosed iTLPD-GI. Intravitreal methotrexate injections were started in the right eye. Brain MRI and lumbar puncture with cytology, MYD88, IL10, and flow cytometry performed at the time of right eye vitreoretinal lymphoma diagnosis revealed no evidence of central nervous system lymphoma, but subsequent bone marrow biopsy demonstrated 5% involvement by iTLPD-GI, JAK2-rearrangment-positive, with a lung nodule on PET-CT. She returned four months later with fatigue, night sweats, and blurry vision in the left eye with vitreous and anterior chamber cellular infiltration and retinal vasculitis. T-cell vitreoretinal lymphoma is rare, and diagnosis can be challenging. Despite inconclusive cytology in this case, interphase fluorescence in situ hybridization detected a JAK2 gene rearrangement, which confirmed involvement by iTLPD-GI and prompted appropriate treatment and workup for recurrent systemic or central nervous system lymphoma.

EFFICACY AND SAFETY OF BTK INHIBITORS IN VITREORETINAL LYMPHOMA: A SINGLE‐CENTER RETROSPECTIVE ANALYSIS OF 24 PATIENTS

Purpose: Vitreoretinal lymphoma (VRL) is a rare subtype of lymphoma. The optimal treatment strategy is not yet defined. 60%–90% of VRL will progress to PCNSL. Therefore, central nervous system (CNS) prophylaxis for VRL patients is critical. Our previous studies have shown that BTK inhibitors monotherapy can replace repeated intravitreal injection of low-dose methotrexate, with rapid effect and a certain preventive value for the CNS. This study aimed to expand the sample size and extend the follow-up time to retrospectively analyze the efficacy and safety of BTK inhibitors in VRL. Method: A total of 24 VRL patients admitted to the Department of Hematology in Beijing Tongren Hospital from May 2020 to December 2022 were included. The clinical characteristics, treatment methods, treatment outcomes, survival status and treatment-related adverse reactions were retrospectively analyzed. Results: The median age was 62 years. There were 18 primary VRLs (PVRLs). The IL-10 in aqueous humor at baseline was significantly increased, and the IL-10/IL-6 ratio was greater than 1. There was no evidence of CNS involvement in 23 patients. All patients were treated with a BTK inhibitors (zanubrutinib 160 mg bid, or orelabrutinib 150 mg qd), and nine of them were also treated with intraocular injection of methotrexate. After 1 month of treatment, 21 patients had CR (87.5%) and 2 patients had PR (8.3%). The IL-10/IL-6 levels of aqueous humor were lower than 1 in all patients. The median duration of BTK inhibitors was 10 months. At a median follow-up of 17 months, 15 patients (62.5%) developed disease progression, including 11 with CNS infiltration and 4 with intraocular recurrence. The median PFS was 11.9 months, and the median OS was not reached. The 1-year PFS rate was 34% and the 1-year OS rate was 96%. The recurrence rate was 33.3% in the combined treatment group and 80.0% in the monotherapy group. Three patients died, all from CNS progression. BTK inhibitors were well tolerated, with grade 1-2 hypertension of 16.7%, grade 1 hypotension of 4.2%, grade 1 joint pain of 8.3%, grade 1 subcutaneous bleeding and ecchymosis of 25.0%. Four patients developed COVID-19 infection and BTK inhibitor medication was suspended. All patients had negative COVID-19 test within 2 weeks and did not develop significant pneumonia. Conclusion: BTK inhibitors showed rapid local control of VRL and were well tolerated. However, monotherapy with BTK inhibitors does not provide adequate central nervous system prophylaxis, and the combination of BTK inhibitors with other drugs, such as high-dose methotrexate, should be explored. The research was funded by: This work was supported by grants from the National Natural Science Foundation of China (grant No. 81873450, 82170181), Beijing Hospitals Authority Youth Programme (code: QML20200201), and Beijing Natural Science Foundation (No.7222027) to Liang Wang. Keywords: aggressive B-cell non-Hodgkin lymphoma, molecular targeted therapies No conflicts of interests pertinent to the abstract.

Tolerability and Efficacy of Multiple Series of Intravitreal Methotrexate Injections for Complex Retinal Detachment Associated with Proliferative Vitreoretinopathy

In this study, we retrospectively reviewed the outcomes of patients treated with one or more series of intravitreal methotrexate (MTX) injections as a surgical adjunct for the prevention of recurrent rhegmatogenous retinal detachment (RRD) related to proliferative vitreoretinopathy (PVR). The study subjects were patients with primary or recurrent RRD associated with grade C PVR, who received one or more series of 9 intravitreal MTX injections. Each series consisted of a single intraoperative MTX injection and then 8 weekly postoperative MTX injections as an off-label surgical adjunct for the prevention of PVR. The primary outcome was the retinal reattachment rate. The secondary outcome was the incidence of treatment-limiting side effects. A total of 14 eyes of 14 patients were identified. The median age was 61 years (range: 9–83), and 43% of the patients were female. Most patients (64%) had a prior primary surgical failure. After one MTX series, 10 eyes (72%) were attached, and 8 (57%) were free of PVR at a median follow-up of 11 months (range: 2–14). All failures after a single MTX series were successfully treated with repeat surgery and a second (n = 4) or third (n = 1) MTX series, for the final reattachment and PVR-free rates of 100%. None of the patients experienced treatment-limiting side effects. Therefore, multiple series of MTX injections can be tolerated if indicated in cases of aggressive PVR threatening the retina.

Primary Vitreoretinal Lymphoma Masquerading as Post-Operative Endophthalmitis in a Pregnant Patient with Longstanding Idiopathic Panuveitis.

To report primary vitreoretinal lymphoma after surgical 0.59 mg fluocinolone acetonide implant (FAi) exchange in a patient treated with adalimumab for idiopathic bilateral panuveitis. Retrospective case review. A 37-year-old woman with bilateral idiopathic panuveitis, who had favorable responses to previous FAi surgical implants, presented with right eye recurrent intraocular inflammation and cystoid macular edema that partially responded to systemic adalimumab. Her FAi was replaced, given her previous favorable response. She developed post-operative ocular inflammation transiently responsive to two serial vitreous taps and injections of intravitreal antimicrobials and then worsening inflammation and new layered flocculant material. Diagnostic vitrectomy showed a few atypical lymphocytes and cultures were negative. At post-diagnostic vitrectomy month 1, flocculant material recurred. Aqueous cytology and flow cytometry revealed large CD45 positive B-cells suspicious for lymphoma. Post-operatively, she revealed that she was pregnant. She was treated with 8 monthly intravitreal methotrexate injections and post-partum consolidation radiotherapy. Subsequent repeat cytology, flow cytometry, and corneal pathology revealed large B-cells that were CD20 positive, and next generation sequencing detected a dominant monoclonal B-cell population, diagnostic of PVRL. 19 months after FAi exchange, she developed an area of enhancement in the lateral aspect of the right frontal lobe on brain MRI, consistent with central nervous system involvement. We present a unique case of PVRL masquerading as post-operative endophthalmitis after FAi exchange in an eye with chronic panuveitis treated with adalimumab immunosuppressive therapy. We hypothesize that there may be a causal relationship between adalimumab and PVRL.

Intravitreal methotrexate in vemurafenib-induced uveitis.

Vemurafenib, a BRAF inhibitor, has revolutionized the prognosis of late-stage melanoma patients, rising at the same time concerns about its potential adverse effects. Here is a case of vemurafenib-induced uveitis, peculiar in both its presentation and management. Case report, diagnostic and therapeutic challenge. Uveitis is a known side effect of vemurafenib. It is generally bilateral, moderate, manageable with topical steroids and does not require cancer therapy cessation. We present a patient who suffered from a unilateral, severe uveitis following vemurafenib treatment that fully recovered thanks to intravitreal methotrexate injections, as conventional corticosteroid therapy was contraindicated. Uveitis can be a serious ocular adverse effect of vemurafenib, while its risks factors and mechanisms remain unknown. As BRAF inhibitors are now used on a regular basis, it is important for clinicians to be aware of this potentially sight-threatening side effect. Intravitreal methotrexate injections may be considered as an effective treatment choice in severe targeted agents-induced uveitis.

Longitudinal Analysis of Ocular Manifestation and Interleukin During Intravitreal Treatment of Vitreoretinal Lymphoma With Methotrexate

To explore the trend of ocular manifestations and interleukin (IL) during the treatment of vitreoretinal lymphoma (VRL), and to evaluate potential effects of different intravitreal administration schedules on the therapeutic response. Interventional comparative non-randomized clinical study. Patients diagnosed with VRL from January 2011 to January 2022 were included. Intravitreal methotrexate (MTX) injections consisting induction, consolidation and maintenance were scheduled. At baseline and each visit, ocular manifestations and interleukin in aqueous humor were recorded. Effects of the variations (e.g. frequency and number) in the injection schedule on the therapeutic response were analyzed. Fifty-eight eyes of 33 patients were treated with intravitreal MTX chemotherapy. A mean (±SD) of 9±3 injections were given; 52 eyes achieved complete remission (CR). IL-10, keratic precipitates and sub-retinal lesions correlated well with the course of treatment (all P <0.001). Initial injection given twice weekly was correlated with a higher rate of CR (36/36) than given once weekly or less frequently (16/22, P=0.011). Ocular progression occurred in 13 eyes of 8 patients. The completion of schedule was correlated with PFS (induction + consolidation + maintenance: 547[335-874] days, induction + consolidation: 355[322-831] days, induction only: 147[116-187.5] days, P<0.001). IL-10 over 50 pg/mL was a feasible threshold for the detection of ocular relapse (sensitivity 100.0%, specificity 95.1%). Keratic precipitates, sub-retinal lesions and IL-10 could serve as indicators for therapeutic response. Intensive initial administration and adequate injection number would help to improve the response and prognosis. IL-10 over 50 pg/mL could help to detect ocular relapse.

Diagnosis, treatment, and prognosis of primary intraocular lymphoma: Single-center real-world clinical experience.

The diagnosis and management of primary intraocular lymphoma (PIOL) remain challenging. This study identified factors indicative of PIOL, described treatment outcomes, and determined modalities to prevent relapse. We included 21 PIOL-diagnosed patients, seven via cytology, 12 via genetic evaluation, and two via interleukin (IL) level measurements, who underwent vitrectomy and received local intravitreal methotrexate (IV-MTX) injection. Clinical outcomes, including treatment response and relapse, were compared between patients receiving IV-MTX alone (n=13) or IV-MTX with systemic high-dose methotrexate (HD-MTX) as prophylaxis (n=8). Twelve ophthalmologic and eight central nervous system (CNS) relapse cases within a median of 20.3 and 11.6 months were shown, regardless of the treatment modalities, with a median progression-free survival of 21.3 (95% confidence interval, 9.5-36.7) months. There was no difference in demographic characteristics between the two groups, except with the poorer performance status in patients in the HD-MTX prophylaxis group. Furthermore, patients demonstrated rapid elevations in the vitreous fluid IL-10/IL-6 cytokine ratio before ophthalmologic and CNS relapse. Therefore, diagnosis should be based on clinical signs and assisted by vitrectomy, cytologic, molecular, and cytokine studies. For PIOL, aggressive systemic treatment equivalent to that of primary CNS lymphoma (PCNSL) is recommended because solely HD-MTX did not prevent or delay CNS relapse. To prevent PIOL relapse in the CNS efficiently, prospective trials with large numbers of patients and advanced therapeutic regimens are necessary. Furthermore, regular clinical follow-up is crucial, and the IL-10/IL-6 ratio can help evaluate relapse promptly.

Clinical utility of cytokine analysis in the diagnosis and efficacy monitoring of vitreoretinal lymphoma.

To investigate the value of cytokine analysis in aqueous humor (AH) for discriminating vitreoretinal lymphoma (VRL) from uveitis and for evaluating the efficacy of intravitreal methotrexate (MTX) injections. This retrospective study was done on 28 VRL patients between 2013 and 2019. AH interleukin (IL)-10, IL-6, IL-8, vascular endothelial growth factor (VEGF), and vascular cell adhesion molecules (VCAM) were measured in 28 VRL patients and 38 uveitis patients. As to the respective examinations for distinguishing VRL from uveitis, the diagnostic accuracy was evaluated by receiver operating characteristic (ROC) curve analysis. The response to treatment was monitored by observing changes in best-corrected visual acuity (BCVA), ocular manifestation, and AH cytokine levels in 21 patients with VRL who had undergo multiple intravitreal injections of MTX. Compared with uveitis patients, VRL patients had higher IL-10 level (P<0.001) and IL-10/IL-6 ratio (P<0.001), whereas patients with uveitis had significantly higher IL-6 level than those with VRL (P=0.003). An ROC analysis was used to identify the diagnostic threshold values for VRL, and it was found that optimal sensitivity and specificity improved to 94.1% and 100%, respectively, for IL-10/IL-6>1.55 and 88.2% and 81.1%, respectively, for IL-10>76.7 pg/mL. In 21 patients who had undergo repeated injections, improvements in BCVA, clinical remission of VRL and continuous decrease in cytokine levels over time were observed. In those patients, the BCVA correlated with the aqueous levels of IL-10 and IL-6 during the course of disease treatment. The combination of the aqueous cytokine profiles can be instrumental for conventional diagnostic methods and for progression monitoring and treatment response.

Inhibition of proliferative vitreoretinopathy by a newly developed methotrexate loaded drug carrier in vitro

PurposeRepeated intravitreal injections of methotrexate for proliferative vitreoretinopathy, a rare ocular condition that can cause vision loss, have shown beneficial effects in recent clinical studies. The purpose of this study was to develop a slow-release, long-term drug carrier composed of the polymer polylactide-co-glycolide and methotrexate that can be injected intravitreally. MethodsThe required composition of the drug carrier was modeled using pharmacokinetic parameters based on current literature. Release kinetics were determined using an ocular pharmacokinetic model. Epiretinal PVR-membranes were harvested during pars plana vitrectomy and subsequently transferred to cell culture. The effect of the drug carrier on cell migration was investigated using time-lapse microscopy and a scratch-induced migration assay. The colorimetric WST-1-assay and a live-dead-assay were performed to determine viability, and the BrdU-assay was applied for proliferation. ResultsThe release profile showed an initial and a final burst of methotrexate with an intervening steady state that lasted 9–11 weeks. It showed inhibitory effects on pathobiological processes in human PVR-cells in vitro. Cell velocity in the time-lapse assay, migration in the scratch assay (p = 0.001), and proliferation in the BrdU assay (p = 0.027) were reduced after addition of the drug carrier. These effects occurred without causing a reduction in viability in the WST-1 assay (p > 0.99) and the live-dead assay. ConclusionThe methotrexate-loaded drug carrier can maintain a stable concentration for 9–11 weeks and influence the pathobiological process of PVR cells in vitro. Therefore, it represents a potential therapeutic orphan drug for PVR.

Aqueous Humor–Derived MYD88 L265P Mutation Analysis in Vitreoretinal Lymphoma: A Potential Less Invasive Method for Diagnosis and Treatment Response Assessment

To investigate whether MYD88 L265P mutation, which is frequently present in vitreoretinal lymphoma, can be detected in aqueous humor, a specimen that can be obtained in a clinic setting, potentially mitigating the need for more invasive vitrectomy procedures, and whether this approach can be used to monitor treatment response. Observational case series. Patients who were diagnosed with biopsy-confirmed or clinically diagnosed vitreoretinal lymphoma or biopsy-confirmed vitritis. We evaluated aqueous humor-derived (AHD) MYD88 L265P mutation during vitreous biopsy or at the initial presentation in the clinic if vitreous biopsy was not feasible. Demographic or clinical features of patients were retrospectively reviewed. Aqueous humor-derived MYD88 L265P mutation was re-evaluated after patients completed a course of intravitreal methotrexate and rituximab injection therapy. The NM_002468.4: c.794T>C (p.L265P) mutation in the MYD88 gene was evaluated in AHD cellular and cell-free DNA using allele-specific polymerase chain reaction. Detection of AHD MYD88 L265P mutation at the initial diagnosis and to monitor the treatment response. Aqueous humor from 18 eyes of 14 patients with biopsy-confirmed or clinically diagnosed vitreoretinal lymphoma and 3 eyes of 3 patients with biopsy-confirmed vitritis were evaluated. Aqueous humor-derived MYD88 L265P mutation was detected in cell-based and cell-free DNA from 15 (83%) of 18 eyes with biopsy-confirmed or clinically diagnosed vitreoretinal lymphoma but not identified in any of the 3 eyes with vitritis. The mutation was less readily detectable in cellular DNA (10 of 18) compared with cell-free DNA (15 of 18). Furthermore, aqueous sampling after intravitreal methotrexate and rituximab injection therapy revealed absence of this mutation after complete response in 7 eyes. The mutation was detected in 1 eye that developed recurrence in a posttreatment window of 6 months. After a mean of follow-up of 9 months, there was no clinical evidence of vitreoretinal lymphoma recurrence in the 7 eyes with no detectable AHD MYD88 L265P mutation. This investigational study suggests that AHD MYD88 L265P can be detected in eyes with lymphoma and may thus serve as a surrogate, less invasive biopsy in the diagnosis and follow-up of vitreoretinal lymphoma, particularly when cell-free DNA is evaluated.

Primary Intraocular Lymphoma: Case Reports and a Review

Primary intraocular lymphoma is a lymphoma that occurs in the eye, and is a subtype of primary central nervous system lymphoma that occurs in the brain, spinal cord, and meninges. It is composed of diffuse large B cell type. The pathophysiology and cause are not known exactly, and future research is needed. However, viral infection is thought to be the cause in immunocompromised patients. Diagnostic methods include fluorescein angiography, retinal tomography, and ocular magnetic resonance imaging. The main diagnostic method is cytopathology, but due to its false-negative rates the interleukin (IL)-10 cytokine, known as a growth factor for malignant B-lymphocytes in primary intraocular lymphoma, can be helpful in diagnosis. In the case of primary intraocular lymphoma, intravitreal methotrexate injection can be performed. Ratio of IL-10/IL-6 is greater than 1 before treatment and decreases to less than 1 after treatment. Although the prognosis is poor, it is expected to increase the survival rate through research on diagnostic methods and intraocular injection treatment combined with systemic chemotherapy and radiation therapy.

Management of primary choroidal lymphoma presenting as extensive serous retinal detachment and salmon patch of bulbar conjunctiva: a case report

BackgroundWe describe the outcome of ultra-low-dose radiotherapy plus intravitreal methotrexate and rituximab injections for a patient with primary choroidal lymphoma who presented with nodular conjunctival salmon patches and extensive serous retinal detachment.Case presentationA 34-year-old Iranian man presented with a nodular patch of bulbar conjunctiva in the right eye, and 1+ vitritis. A nearly complete shallow serous retinal detachment, retinal folds, and multifocal yellow choroidal infiltrates were seen during a fundus examination of the right eye. Enhanced depth imaging optical coherence tomography revealed macular retinal folds and an uneven, undulating, “seasick” appearance of the choroidal surface with choriocapillaris compression, intraretinal and subretinal fluid, and clusters of optically dense material at the outer retinal level. An incisional biopsy of the conjunctival lesion confirmed the diagnosis of primary choroidal lymphoma with epibulbar involvement. The patient was treated with ultra-low-dose “boom-boom” radiation (4 Gy delivered in two fractions over two consecutive days) as well as intravitreal methotrexate and rituximab injections. After a year, the lesions had completely disappeared, with no adverse effects or recurrence.ConclusionUltra-low-dose (boom-boom) radiotherapy combined with intravitreal chemotherapy and/or immunotherapy may be an effective treatment for primary choroidal lymphoma with anterior epibulbar extension and diffuse subretinal fluid with favorable response and minimal side effects.