A minimally invasive, combined approach to the recurrent/recalcitrant sino-orbital mucocele.

PURPOSE: To evaluate the results of a minimally invasive combined endoscopic and eyelid crease/medial suprabrow incision approach in collaboration with oculoplastic and sinus surgeons for the treatment of recurrent/recalcitrant sino-orbital mucoceles. METHODS: Eighteen cases of recurrent/recalcitrant sino-orbital mucoceles, treated in collaboration with oculoplastic and sinus surgeons at the University of Michigan, were retrospectively reviewed. The recurrence of mucocele, reduction in proptosis, and complications were evaluated. RESULTS: The mean age at the time of surgery was 49 years (range: 17-76 years). All cases had a history of previous sinus or orbital surgeries for mucoceles. Among 18 cases, eight were due to chronic sinus infections, six due to trauma, three due to Schneiderian papilloma, and one case was secondary to an inflammatory sinus disease. Thirteen cases (72%) presented with orbital or facial cellulitis, while five cases (38%) experienced periocular swelling and limited extraocular motility. Following a mean follow-up of 19 months (range: 1-76 months)), recurrence was observed in two cases (11%): one in a cystic fibrosis patient with chronic sinusitis, and the other in a case of Schneiderian papilloma. The mean pre-operative proptosis in the affected eye was 2.78 mm, with an average decrease of 2.33 mm after surgery. Complications occurred in two cases, including one case of hypoesthesia in the forehead and one case of post-operative strabismus. CONCLUSION: Our series of 18 cases of recurrent/recalcitrant mucoceles, with only two cases of recurrence, demonstrates that this minimally invasive approach can be successfully employed for advanced sino-orbital disease, with a low rate of adverse outcomes and aesthetically pleasing results.

15-Gene Expression Profile and PRAME as Integrated Prognostic Test for Uveal Melanoma: First Report of Collaborative Ocular Oncology Group Study No. 2 (COOG2.1).

PURPOSE: Validated and accurate prognostic testing is critical for precision medicine in uveal melanoma (UM). Our aims were to (1) prospectively validate an integrated prognostic classifier combining a 15-gene expression profile (15-GEP) and PRAME RNA expression and (2) identify clinical variables that enhance the prognostic accuracy of the 15-GEP/PRAME classifier. MATERIALS AND METHODS: This study included 1,577 patients with UM of the choroid and/or ciliary body who were enrolled in the Collaborative Ocular Oncology Group Study Number 2 (COOG2) and prospectively monitored across 26 North American centers. Test results for 15-GEP (class 1 or class 2) and PRAME expression status (negative or positive) were available for all patients. The primary end point was metastasis-free survival (MFS). RESULTS: 15-GEP was class 1 in 1,082 (68.6%) and class 2 in 495 (31.4%) patients. PRAME status was negative in 1,106 (70.1%) and positive in 471 (29.9%) patients. Five-year MFS was 95.6% (95% CI, 93.9 to 97.4) for class 1/PRAME(-), 80.6% (95% CI, 73.9 to 87.9) for class 1/PRAME(+), 58.3% (95% CI, 51.1 to 66.4) for class 2/PRAME(-), and 44.8% (95% CI, 37.9 to 52.8) for class 2/PRAME(+). By multivariable Cox proportional hazards analysis, 15-GEP was the most important independent predictor of MFS (hazard ratio [HR], 5.95 [95% CI, 4.43 to 7.99]; P < .001), followed by PRAME status (HR, 1.82 [95% CI, 1.42 to 2.33]; P < .001). The only clinical variable demonstrating additional prognostic value was tumor diameter. CONCLUSION: In the largest prospective multicenter prognostic biomarker study performed to date in UM to our knowledge, the COOG2 study validated the superior prognostic accuracy of the integrated 15-GEP/PRAME classifier over 15-GEP alone and clinical prognostic variables. Tumor diameter was found to be the only clinical variable to provide additional prognostic information. This prognostic classifier provides an advanced resource for risk-adjusted metastatic surveillance and adjuvant trial stratification in patients with UM.

Staged Excision Technique for Periocular Cutaneous Melanoma: Long-Term Outcomes of the Square Procedure.

PURPOSE: To examine the long-term outcome of the staged excision via the square procedure for the treatment of periocular thin cutaneous melanoma. METHODS: A retrospective chart review of 95 periocular cutaneous melanoma-in-situ and microinvasive melanoma tumors that were treated with the square procedure between April 1, 1994 and December 31, 2018 at the University of Michigan. Demographic and clinical data were evaluated. RESULTS: Of 95 cases, 19 (20%) were atypical junctional melanocytic proliferation with features of early melanoma-in-situ, 63 (66.3%) were melanoma-in-situ and 13 (13.7) were microinvasive melanoma with Breslow depth less than 1 mm. Tumor-free margins were achieved with a median margin of 10 mm (range 5-40 mm). Most cases (68.4%) required multiple excision stages. Surgical revision was necessary in 17.9% of cases and was associated with larger defect size. Local recurrence was noted in 8 patients (8.4%) at a median of 42 months postreconstruction. No tumor characteristics were found to predict recurrence. CONCLUSIONS: The square procedure for periocular melanoma offers an 8.4% recurrence rate, consistent with literature reports on similar staged excision approaches. The staged excision provides an excellent option for comprehensive margin review and tumor control with acceptable cosmetic results after reconstruction.

Establishment and characterization of cMYB-expressing human salivary adenoid cystic carcinoma cell lines (UM-HACC-14, UM-HACC-6) and matching patient-derived xenograft model (UM-PDX-HACC-14).

OBJECTIVE: Limited availability of authentic human adenoid cystic carcinoma (ACC) cell lines has hindered progress in understanding mechanisms underpinning the biology of this disease and the development of safe and effective therapies. STUDY DESIGN: Surgical human ACC specimens (UM-HACC-6, UM-HACC-14) were dissociated into single cell suspensions and cultured in fibronectin-coated flasks. Alternatively, tumor fragments were transplanted subcutaneously into female immunodeficient (SCID) mice to establish patient-derived xenograft tumors (PDX; UM-PDX-HACC-14). RESULTS: Both ACC cell lines showed continuous growth in monolayers for over 100 passages. Total RNA-Seq, RT-PCR, and FISH analysis revealed that both are MYB-NFIB fusion negative. Western blots revealed passage-dependent expression of E-Cadherin, PCNA, p63, phospho-c-MYB, and NFIB. Both, UM-HACC-14 and UM-HACC-6 cells exhibited tumorigenic potential when injected orthotopically into mouse submandibular glands. CONCLUSION: UM-HACC-14, patient-matching UM-PDX-HACC-14, and the UM-HACC-6 cell line are new, authenticated preclinical models of ACC that are well suited for mechanistic and developmental therapeutics studies.

Conjunctival Apocrine Hidrocystoma: A Case Report and Review of Literature.

PURPOSE: To describe the clinical features of a conjunctival apocrine hidrocystoma that developed 6 decades after a strabismus surgery and review existing literature on apocrine hidrocystomas of the conjunctiva and caruncle. METHODS: Case report and review of literature on conjunctival apocrine hidrocystomas. RESULTS: A 71-year-old man with a history of strabismus surgery as a child presented with a cystic lesion on the nasal conjunctiva and caruncle for 1 year. Excision of the lesion showed a unilocular cavity lined by a double layer of cells with the hallmark finding of apical decapitations, confirming a diagnosis of apocrine hidrocystoma. Seven additional cases of conjunctival and caruncular apocrine hidrocystomas were reviewed. All cases presented after 50 year of age. Most cases presented nasally or within the caruncle and had a pigmented appearance. No other reported cases had a history of trauma or surgery. All cases were treated with surgical excision without recurrence. CONCLUSIONS: History of strabismus surgery or conjunctival trauma may lead to ectopic deposition of apocrine glands that may contribute to the formation of an apocrine hidrocystoma.

Occlusive Vasculitis Following Intravitreal Rituximab Injection for Primary Vitreoretinal Lymphoma.

PURPOSE: We report three cases of occlusive vasculitis following intravitreal rituximab therapy for biopsy-proven primary vitreoretinal lymphoma (PVRL), one of which was following an injection of the biosimilar Riabni (rituximab-arrx, AmGen) and two of which were following an injection of Rituxan (rituximab, Genentech). METHODS: Case series. RESULTS: Three cases of occlusive vasculitis confirmed with fluorescein angiography are reported 5 days, 8 days, and 3.5 weeks following intravitreal injection of rituximab. The initial vision was poor (20/500, 20/150, and light perception), but vision recovered to baseline in two cases, and remained poor in the case of combined artery and vein occlusion. CONCLUSION: Occlusive vasculitis is a rarely reported but potential complication of intravitreal rituximab therapy in patients who have been previously treated with the agent and may have delayed onset. A low threshold for fluorescein angiography as a diagnostic test for post-injection vision loss and prompt treatment with topical and/or oral steroids should be considered.

Posterior Uveitis in Ocular-Involving Chronic Lymphocytic Leukemia and the Utility of Negative MYD88 L265P Testing in the Diagnosis.

Introduction: The aim of this study was to investigate if a negative test result for MYD88 L265P mutation, associated with vitreoretinal lymphoma (VRL) and primary CNS lymphoma, in liquid biopsies from intraocular fluids can be a useful adjuvant test to diagnose chronic lymphocytic leukemia in clinically challenging cases. Case Presentations: We selected patients with a past medical history or examinations findings suspicious for intraocular lymphoma. We evaluated both vitreous and aqueous humor-derived (AHD) MYD88 L265P mutation from patients that had suspected intraocular lymphoma that warranted a liquid biopsy procedure. Gold-standard cytopathology, flow cytometry, and gene rearrangement studies were also performed. All 4 patients had negative AHD MYD88 L265P mutation testing. Gold-standard testing (cytology) either showed paucicellular specimens (1/4) or specimens with high background inflammation (3/4). One case showed a rare B-cell clonal population (CD5+, Kappa-restricted by flow cytometry), but this was not sufficient to make any definitive diagnosis. All patients were subsequently initiated on systemic therapy and had improvement in their disease burden. Conclusions: Negative AHD MYD88 L265P mutation testing can serve as an adjuvant molecular test to diagnose difficult cases of intraocular CLL.

Oral Hypoxia-Inducible Factor 2α Inhibitor Belzutifan in Ocular von Hippel-Lindau Disease: Subgroup Analysis of the Single-Arm Phase 2 LITESPARK-004 Study.

PURPOSE: To report the efficacy of the oral hypoxia-inducible factor 2α inhibitor belzutifan in participants with von Hippel-Lindau disease-associated retinal hemangioblastomas in the LITESPARK-004 study. DESIGN: Subgroup analysis of the phase 2, single-arm, open-label LITESPARK-004 study. PARTICIPANTS: Adults with 1 or more von Hippel-Lindau disease-associated measurable renal cell carcinoma tumors not requiring immediate surgical intervention were eligible. METHODS: Participants received oral belzutifan 120 mg once daily until disease progression or unacceptable treatment-related toxicity. MAIN OUTCOME MEASURES: Efficacy of belzutifan in retinal hemangioblastomas was a secondary end point, measured as response (improved, stable, or progressed) by independent reading center-certified graders based on color fundus imaging performed every 12 weeks using the investigator's preferred imaging standards. Additional assessments, where available, included OCT and ultra-widefield fluorescein angiography. RESULTS: Among 61 participants in LITESPARK-004, 12 had 1 or more evaluable active retinal hemangioblastomas in 16 eyes at baseline per independent reading center. As of April 1, 2022, the median follow-up for participants with ocular von Hippel-Lindau disease at baseline was 37.3 months. All 16 eyes were graded as improved, with a response rate of 100.0% (95% confidence interval, 79.4%-100%). No new retinal hemangioblastomas or ocular disease progression were reported as of data cutoff date. Eight participants underwent additional multimodal eye assessments performed at the National Institutes of Health study site. Among this subgroup, 10 of 24 hemangioblastomas in 8 eyes of 6 participants measured 500 µm or more in greatest linear dimension at baseline and were analyzed further. All 10 hemangioblastomas had a mean area reduction of 15% or more by month 12 and of 30% or more by month 24. CONCLUSIONS: Belzutifan showed promising activity against ocular von Hippel-Lindau disease, including capacity to control retinal hemangioblastomas, with effects sustained for more than 2 years while treatment is ongoing. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Immunotherapy for a Choroidal Pigmented Lesion.

A 51-year-old male with a a history of BRAF V600 E mutation-positive, superficial spreading-type cutaneous melanoma on the chest with metastasis to a sentinel lymph node had a 4-week history of redness and swelling of the right temporal bulbar conjunctiva and was referred for evaluation of a choroidal lesion in the right eye. What would you do next?

Targeted therapy in ophthalmic oncology: The current status.

There have been rapid advancements in the field of ocular oncology for the diagnosis and management of intraocular, adnexal, and orbital tumors. Targeted therapy is in the forefront of medical research in all fields including ocular oncology. Targeted therapy include drugs that target specific genetic mutations, pathways or proteins involved in the development of cancer. In contrast to traditionally used chemotherapy, drugs used in targeted therapy are highly specific for tumor cells and preserve the function of normal cells. This review aims to familiarize ophthalmologists with the drugs that are currently approved or undergoing clinical trials for use in ocular oncology. Targeted therapy is particularly useful for locally advanced or metastatic tumors, including but not limited to eyelid and periocular basal cell carcinoma, periocular cutaneous and conjunctival squamous cell carcinoma, ocular adnexal lymphoma, conjunctival melanoma, and uveal melanoma. The results are promising with improved survival outcomes and better tolerability than chemotherapeutic drugs.

Multispecialty Management of Metastatic Colon Adenocarcinoma Involving the Extraocular Muscles: Primary Excision and Simultaneous Treatment of Strabismus With a Review of the Literature.

Metastatic colon adenocarcinoma involving the extraocular muscles is extremely rare. It usually develops following the diagnosis of the systemic disease and therefore, management and treatment require a multispecialty approach. Within this manuscript, we provide a summary of cases of orbital metastasis secondary to colon cancer. We further discuss a detailed case of a 42-year-old male patient who developed recent-onset diplopia in the left gaze. Orbital CT imaging showed a localized, well-circumscribed enlargement of the right medial rectus muscle. The biopsy of the right medial rectus showed adenocarcinoma originating from the gastrointestinal system. Further workup revealed colon adenocarcinoma with multiple metastatic sites. The patient started systemic chemotherapy. After 2 months of chemotherapy (5-fluouracil, oxaliplatin, irinotecan, and leucovorin), all systemic metastatic sites regressed; however, his medial rectus muscle continued to grow, causing compressive optic neuropathy. The patient underwent excisional biopsy of the right medial rectus muscle with simultaneous repair of the strabismus with transposition of superior and inferior recti muscles. He continued with systemic chemotherapy. Follow up in 1 year revealed no local orbital tumor recurrence with excellent visual acuity and no diplopia in primary gaze.

SUPRACHOROIDAL SPACE INJECTION TECHNIQUE: Expert Panel Guidance.

PURPOSE: To develop professional guidelines for best practices for suprachoroidal space (SCS) injection, an innovative technique for retinal therapeutic delivery, based on current published evidence and clinical experience. METHODS: A panel of expert ophthalmologists reviewed current published evidence and clinical experience during a live working group meeting to define points of consensus and key clinical considerations to inform the development of guidelines for in-office SCS injection. RESULTS: Core consensus guidelines for in-office SCS injection were reached and reported by the expert panel. Current clinical evidence and physician experience supported SCS injection as a safe and effective method for delivering retinal and choroidal therapeutics. The panel established consensus on the rationale for SCS injection, including potential benefits relative to other intraocular delivery methods and current best practices in patient preparation, pre- and peri-injection management, SCS-specific injection techniques, and postinjection management and follow-up. CONCLUSION: These expert panel guidelines may support and promote standardization of SCS injection technique, with the goal of optimizing patient safety and outcomes. Some aspects of the procedure may reasonably be modified based on the clinical setting and physician judgment, as well as additional study.

Relationships between internet addiction, smartphone addiction, sleep quality, and academic performance among high-school students.

OBJECTIVE: In this study, we aimed to evaluate the relationships between Internet addiction, smartphone addiction, sleep quality, and academic success. METHODS: In this cross-sectional study, high-school students were surveyed to evaluate sleep quality, Internet addiction, and smartphone addiction. Students were queried about their demographics, and grade averages from the previous term were taken as an indicator of academic success. RESULTS: A total of 1,959 students were enrolled in this study, with 1,034 (52.8%) girls and 925 (47.2%) boys, and the median age of the participants was 16 (13-21) years. Multivariate analyses found that poor sleep quality in students who did not have breakfast before going to school was 1.58 times higher than those who did (p<0.001). Students who stayed in a dormitory had 1.79 times more poor sleep quality than those who stayed with their family, and a one-unit increase in the total score of the Young's Internet Addiction Test short form resulted in a 1.08-fold increase (both, p<0.001). CONCLUSION: Our study has shown that students' sleep quality was predicted to be lower if they stayed in a dormitory and skipped breakfast. In addition, Internet and smartphone addictions have a negative effect on sleep quality and academic performance.

Bilateral Choroidal Detachments Associated with Perinuclear Anti-Neutrophil Cytoplasmic Antibodies (P-ANCA) - Associated Vasculitis.

PURPOSE: To report an uncommon, isolated presentation of bilateral choroidal detachments in a patient diagnosed with P-ANCA-associated vasculitis and to highlight the importance of an inflammatory work-up in such cases. METHODS: Case report. RESULTS: A 70-year-old male with a past medical history of autoimmune hepatitis presented with a sudden decrease in vision in both eyes. Over the course of the previous decade, he had experienced recurrent attacks of episcleritis, which were successfully managed with topical corticosteroid eye drops. The patient was diagnosed with bilateral detachments without accompanying scleritis or intraocular inflammation. Inflammatory markers revealed high P-ANCA and anti-MPO levels, confirming the diagnosis of P-ANCA-associated vasculitis. Treatment with systemic rituximab and corticosteroids led to the resolution of the choroidal detachment in both eyes. A 40-month follow-up confirmed the sustained resolution of the detachments. CONCLUSION: Choroidal detachment without other extraocular/intraocular inflammation can be associated with P-ANCA-associated vasculitis, a previously under-reported link. It is important to consider an inflammatory work-up for patients presenting with choroidal detachment to rule out conditions like P-ANCA-associated vasculitis.

Use of Cemiplimab, an Immune Checkpoint Inhibitor for Conjunctival Intraepithelial Neoplasia.

PURPOSE: Immune checkpoint inhibitors (ICIs) have been recently introduced for the treatment of locally unresectable conjunctival squamous cell carcinoma. We present 2 cases with conjunctival intraepithelial neoplasia (CIN) who were treated with ICIs. METHODS: A report of 2 cases with CIN who were treated with systemic cemiplimab (350 mg IV every 3 weeks). RESULTS: A 70-year-old man was treated with cemiplimab for metastatic cutaneous squamous cell carcinoma. The pre-existing CIN continued to progress over the nasal bulbar conjunctiva and cornea, while the other metastatic sites, including parotid glands, and neck lymph nodes showed a complete response after 16 cycles of treatment. An 84-year-old woman had bilateral diffuse CIN involving bulbar and lower eyelid palpebral conjunctiva. Cemiplimab was started because of the extent of involvement. While the bulk of CIN was reduced, it progressed over the cornea and forniceal conjunctiva on OU after 10 cycles of treatment. Excisional biopsies of conjunctival lesions after cemiplimab confirmed CIN in both patients. CONCLUSIONS: Although conjunctival squamous cell carcinoma tumors are reported to be highly responsive to ICIs, a similar effect has not been observed in 2 patients with CIN. Further studies are needed to evaluate ICIs in the management of CIN.

Targeted Therapy and Immunotherapy for Advanced Malignant Conjunctival Tumors: Systematic Review.

PURPOSE: To review the outcomes of targeted therapy and immunotherapy in advanced conjunctival tumors, including conjunctival squamous cell carcinoma, conjunctival melanoma, and conjunctival lymphoma. METHODS: A Pubmed database systematic search was performed between January 1999 and December 2022. The literature search was limited to studies published in English. RESULTS: This review included 142 patients with advanced malignant conjunctival tumors from 42 articles. In the conjunctival squamous cell carcinoma group, 2 cases of advanced conjunctival squamous cell carcinoma treated with epidermal growth factor receptor inhibitors showed significant tumor size improvement after 7.5 months of follow-up. Among 7 cases treated with systemic immunotherapy, 5 cases (72%) had complete response (CR), 1 case (14%) showed partial response (PR), and 1 case (14%) had stable disease (SD) after 16 months. In the conjunctival melanoma group, among 18 cases treated with combined v-raf murine sarcoma viral oncogene homolog B1/mitogen-activated extracellular signal-regulated kinase inhibitors, 6 (33%) had CR, 5 (28%) had PR, 2 (11%) had SD, and 5 (28%) had progressive disease after 24.8 months of follow-up. Of 44 conjunctival melanoma cases treated with immunotherapy, 12 (28%) had CR, 9 (20%) had PR, 7(16%) had SD, and 16 (36%) had progressive disease after 14.2 months. Systemic Rituximab treatment for conjunctival lymphoma cases resulted in CR in 21 patients (63%), PR in 11 patients (33%), and SD in 1 patient (3%) after 20.5 months of follow-up. Intralesional Rituximab injections in 38 conjunctival lymphoma cases showed CR in 28 patients (75%), PR in 7 patients (19%), SD in 1 patient (2%), and progressive disease in 2 patients (4%) after 20.4 months of follow-up. CONCLUSIONS: Despite limited clinical case reports and short-term follow-ups, targeted therapy and immunotherapy have shown promising results for advanced malignant conjunctival tumors.

Review of Targeted Therapy, Vismodegib, for the Treatment of Periocular Basal Cell Carcinoma.

PURPOSE: Periocular locally advanced basal cell carcinoma (POLA-BCC) is characterized by orbital involvement and/or extensive invasion of periocular structures. Hedgehog pathway inhibitors have been used for POLA-BCC with promising outcomes. METHODS: The authors reviewed 11 articles published in English literature from January 2012 to July 2022 and reported the outcomes of patients with POLA-BCC who were treated with vismodegib. RESULTS: A total of 384 patients were treated with vismodegib. The mean age was 72 years, and the median treatment duration was 9 months. The overall response rate was 75% with a median follow-up time of 14.4 months. Following vismodegib treatment, the median number of patients who required adjuvant surgery was 43% with a median time to surgery of 6.5 months. The exenteration rate was 6% (overall 8 patients). In total 93.7% of patients experienced grade I adverse events, 26.7% to 37.5% grade II, 8.8% to 10% grade III-IV, and 0.8% to 4.8% grade V. Major side effects included dysgeusia (30-100%), muscle spasm (15-100%), alopecia (47-75%), weight loss (23-83%), and decreased appetite (19-42%). The median percentage of patients who discontinued treatment due to toxicity was 29% with a median interval of 5 months before the development of side effects. The median recurrence rate following discontinuation of vismodegib was 7.8% with a median recurrence duration of 20 months. CONCLUSIONS: In patients with POLA-BCC, vismodegib, a hedgehog pathway inhibitor, provided high rates of orbital preservation, reducing exenteration rates to 6%. Neoadjuvant therapy with vismodegib can also be suggested for patients with POLA-BCC. While extremely effective, side effects lead to temporary or permanent discontinuation of vismodegib in small numbers of patients.

INTRAVITREAL MELPHALAN INJECTION AS A SECOND-LINE LOCAL THERAPY IN VITREORETINAL LYMPHOMA: Case Series.

PURPOSE: To evaluate the effectiveness and safety of intravitreal melphalan (IVM) injection therapy in vitreoretinal lymphoma. METHODS: Eight eyes of five biopsy-proven vitreoretinal lymphoma patients who were treated with IVM injection as a second-line therapy after intravitreal methotrexate and rituximab injections were retrospectively evaluated between January 2011 and March 2023. RESULTS: The medical records of five vitreoretinal lymphoma patients (mean age of 62 years at the diagnosis) including 4 (80%) female patients and 1 (20%) male patient were retrospectively analyzed. Three patients (60%) either had a history of central nervous lymphoma or developed it during the follow-up. Patients were previously treated with a mean of five cycles of monthly intravitreal methotrexate and rituximab injections. All eyes showed complete response by the disappearance of vitreal and/or subretinal neoplastic cells within 6 weeks after IVM injections (range, 1-4 injections per eye). Of 12 IVM injections, 3 (25%) injections were associated with macular edema diagnosed on optical coherence tomography at 1-month follow-up and resolved spontaneously within 5 months. The IVM administration induced new retinal pigment epithelium changes in three eyes (37%). CONCLUSION: Intravitreal melphalan injection may be effective in the management of vitreoretinal lymphoma as a second-line local therapy. Randomized clinical trials with larger numbers of patients are needed to establish the efficacy, treatment protocol, and safety of IVM injection.