Vitreoretinal Lymphoma Masquerading as Central Serous Chorioretinopathy.

The following is a case of vitreoretinal lymphoma masquerading as central serous chorioretinopathy (CSCR). A 74-year-old man presented with blurred vision in the left eye with unilateral subretinal fluid in the setting of exogenous corticosteroid use, which was diagnosed as CSCR and resolved with corticosteroid cessation. He later experienced a similar self-limited episode in the right eye. Subsequently, he developed bilateral vitritis with yellow-white subretinal pigment epithelial infiltrates. Vitreous biopsy confirmed a diagnosis of large B-cell lymphoma. Vitreoretinal lymphoma can masquerade as a number of ocular pathologies, including CSCR. [Ophthalmic Surg Lasers Imaging Retina 2024;55:XX-XX.].

DOTATATE PET/MR Imaging Differentiates Secondary-Progressive from de Novo World Health Organization Grade 3 Meningiomas.

BACKGROUND AND PURPOSE: WHO grade 3 meningiomas are rare and poorly understood and have a higher propensity for recurrence, metastasis, and worsened clinical outcomes compared with lower-grade meningiomas. The purpose of our study was to prospectively evaluate the molecular profile, PET characteristics, and outcomes of patients with World Health Organization grade 3 meningiomas who were imaged with gallium 68 (68Ga) DOTATATE PET/MR imaging. MATERIALS AND METHODS: Patients with World Health Organization grade 3 meningiomas enrolled in our prospective observational cohort evaluating the utility of (68Ga) DOTATATE PET/MR imaging in somatostatin receptor positive brain tumors were included. We stratified patients by de novo-versus-secondary-progressive status and evaluated the differences in the PET standard uptake value, molecular profiles, and clinical outcomes. RESULTS: Patients met the inclusion criteria (secondary-progressive: 7/14; de novo: 7/14). The secondary-progressive cohort had a significantly higher per-patient number of surgeries (4.1 versus 1.6; P = .011) and trended toward a higher number of radiation therapy courses (2.4 versus 1.6; P = .23) and cumulative radiation therapy doses (106Gy versus 68.3Gy; P = .31). The secondary-progressive cohort had a significantly lower progression-free survival compared with the de novo cohort (4.8 versus 37.7 months; P = .004). Secondary-progressive tumors had distinct molecular pathology profiles with higher numbers of mutations (3.5 versus 1.2; P = .024). Secondary-progressive tumors demonstrated higher PET standard uptake values (17.1 versus 12.4; P = .0021). CONCLUSIONS: Our study confirms prior work illustrating distinct clinical outcomes in secondary-progressive and de novo World Health Organization grade 3 meningiomas. Furthermore, our findings support (68Ga) DOTATATE PET/MR imaging as a useful management strategy in World Health Organization grade 3 meningiomas and provide insight into meningioma biology, as well as clinical management implications.

Shifting the landscape: The role of IDH inhibitors in glioma cell fate.

In this issue of Cancer Cell, Spitzer and colleagues demonstrate the role of IDH inhibitors on IDHmutant gliomas in reducing proliferation and enhancing cell differentiation toward an astrocytic-like state, thus altering neurodevelopmental pathways. Despite clinical promise, unresolved questions regarding mechanisms of action and resistance underline the need for further research for treatment optimization.

Glioblastoma: Not Just Another Cancer.

SUMMARY: This commentary urges a paradigm shift in how we approach research and drug development for glioblastoma, reimagining it as an aberrant brain-like organ, distinct from other cancers, to inspire innovative treatment strategies and interdisciplinary collaboration, addressing the minimal progress in extending glioblastoma patient survival despite years of research and investment.

Stem cell modeling of nervous system tumors.

Nervous system tumors, particularly brain tumors, represent the most common tumors in children and one of the most lethal tumors in adults. Despite decades of research, there are few effective therapies for these cancers. Although human nervous system tumor cells and genetically engineered mouse models have served as excellent platforms for drug discovery and preclinical testing, they have limitations with respect to accurately recapitulating important aspects of the pathobiology of spontaneously arising human tumors. For this reason, attention has turned to the deployment of human stem cell engineering involving human embryonic or induced pluripotent stem cells, in which genetic alterations associated with nervous system cancers can be introduced. These stem cells can be used to create self-assembling three-dimensional cerebral organoids that preserve key features of the developing human brain. Moreover, stem cell-engineered lines are amenable to xenotransplantation into mice as a platform to investigate the tumor cell of origin, discover cancer evolutionary trajectories and identify therapeutic vulnerabilities. In this article, we review the current state of human stem cell models of nervous system tumors, discuss their advantages and disadvantages, and provide consensus recommendations for future research.

Crystalline Retinopathy Following Intravitreal Clindamycin.

This case report describes a 74-year-old woman who developed a crystalline retinopathy following intravitreal injection of clindamycin. The patient presented with ocular toxoplasmosis in the left eye but was allergic to sulfa medications, so she was treated with intravitreal clindamycin. Subsequently, fine refractile yellow-white crystals were observed on examination of the left macula. Optical coherence tomography localized the crystals to the posterior hyaloid. Intravitreal clindamycin should be considered in the differential diagnosis of crystalline retinopathy. [Ophthalmic Surg Lasers Imaging Retina 2024;55:168-170.].

Tissue factor is a critical regulator of radiation therapy-induced glioblastoma remodeling.

Radiation therapy (RT) provides therapeutic benefits for patients with glioblastoma (GBM), but inevitably induces poorly understood global changes in GBM and its microenvironment (TME) that promote radio-resistance and recurrence. Through a cell surface marker screen, we identified that CD142 (tissue factor or F3) is robustly induced in the senescence-associated ß-galactosidase (SA-ßGal)-positive GBM cells after irradiation. F3 promotes clonal expansion of irradiated SA-ßGal+ GBM cells and orchestrates oncogenic TME remodeling by activating both tumor-autonomous signaling and extrinsic coagulation pathways. Intratumoral F3 signaling induces a mesenchymal-like cell state transition and elevated chemokine secretion. Simultaneously, F3-mediated focal hypercoagulation states lead to activation of tumor-associated macrophages (TAMs) and extracellular matrix (ECM) remodeling. A newly developed F3-targeting agent potently inhibits the aforementioned oncogenic events and impedes tumor relapse in vivo. These findings support F3 as a critical regulator for therapeutic resistance and oncogenic senescence in GBM, opening potential therapeutic avenues.

A multicenter, phase 1, dose escalation clinical trial (G-FORCE-1) of XRT, RRx-001 and temozolomide followed by temozolomide +/- RRx-001 in newly diagnosed glioblastoma.

Introduction: The current standard of care for newly diagnosed glioblastoma (GBM) is maximum surgical resection followed by concurrent treatment with temozolomide (TMZ) and radiotherapy (RT) and then six to twelve cycles of maintenance TMZ. RRx-001, an NLRP3 inhibitor and nitric oxide (NO) donor with chemoradiosensitizing, vascular normalizing and macrophage repolarizing properties, is currently in a Phase III trial for small cell lung cancer (SCLC). The purpose of this non-randomized trial was to establish the safety and look for a signal of clinical activity of RRx-001 as an add-on to RT and TMZ in patients with newly diagnosed glioblastoma. Methods: In this non-randomized, open-label, two part trial called G-FORCE-1 (NCT02871843), the first four cohorts of adult patients with histologically confirmed high grade gliomas received fractionated radiotherapy (60 Gy in 30 fractions over 6 weeks), daily 75 mg/m2 temozolomide and escalating doses of once weekly RRx-001 from 0.5 mg to 4 mg according to a 3+3 design followed by a 6 week no treatment interval and then standard maintenance TMZ (150 mg/m2 Cycle 1 and 200 mg/m2 in subsequent cycles) until disease progression. The second two cohorts of patients received fractionated radiotherapy (60 Gy in 30 fractions over 6 weeks), daily 75 mg/m2 temozolomide and once weekly RRx-001 4 mg followed by a 6 week no treatment interval and then two different maintenance schedules until disease progression according to the same 3+ 3 design: 1. 0.5 mg RRx-001 once weekly + 100 mg/m2 TMZ 5 days/week for up to 6 cycles of therapy; 2. 4 mg RRx-001 once weekly + 100 mg/m2 TMZ 5 days/week for up to 6 cycles of therapyThe primary endpoint was the recommended dose/maximally tolerated dose of the combination of RRx-001, TMZ and RT. Secondary endpoints were overall survival, progression free survival, objective response rate, duration of response and clinical benefit response. Results: A total of 16 newly diagnosed glioblastoma patients were enrolled. No dose limiting toxicities were observed and no MTD was reached. The recommended dose is 4 mg. After 24 months of follow up the median OS was 21.9 months (95% CI: 11.7 - NA). PFS median was 8 months (95% CI: 5 - NA). The overall response rate was 18.8% (3 PR out of 16) and the disease control rate was 68.8% (3 PR, 8 SD out of 16). Conclusions: The addition of RRx-001 to TMZ and RT and to TMZ during maintenance was safe and well-tolerated and deserves further study.

Stability of Vancomycin and Ceftazidime With Prolonged Storage at -20°C.

BACKGROUND AND OBJECTIVE: Vancomycin and ceftazidime are commonly used intravitreal antibiotics for suspected bacterial endophthalmitis. Many retina surgical practices prepare aliquoted individual doses in syringes that are then stored frozen for future use, but this practice has not been well studied. This investigation aims to examine the stability of frozen vancomycin and ceftazidime. MATERIALS AND METHODS: Samples of drugs were reconstituted monthly and placed in a -20°C freezer. At the end of 3 months and again at 6 months, a newly reconstituted drug constant was created and compared to a newly created reference sample. The frozen samples were compared to a freshly produced drug solution. Using high-performance liquid chromatography (HPLC), the peak heights were compared to evaluate stability. RESULTS: The vancomycin reference sample was 100 ± 1.67%. Values over time were 97.4 ± 0.75%, 98.8 ± 0.44%, 102.1 ± 0.4%, 100.5 ± 0.12%, 101.8 ± 0.12, 101.5 ± 0.11, and 100.6 ± 1.87 for 1, 2, 3(A), 3(B), 4, 5, and 6 months, respectively. The ceftazidime reference sample was 100 ± 1.8%. Values over time were 100.7 ± 1.78%, 100.0 ± 1%, 102.3 ± 1.55%, 117.5 ± 11.6%, 112.8 ± 1.64%, 123 ± 2.8%, and 117 ± 2.5% for 1, 2, 3(A), 3(B), 4, 5, and 6 months, respectively. CONCLUSION: Both vancomycin and ceftazidime were stable over 6 months under frozen conditions at -20°C. [Ophthalmic Surg Lasers Imaging Retina 2023;54:281-283.].

Microenvironment-Driven Dynamic Chromatin Changes in Glioblastoma Recapitulate Early Neural Development at Single-Cell Resolution.

The tumor microenvironment is necessary for recapitulating the intratumoral heterogeneity and cell state plasticity found in human primary glioblastoma (GBM). Conventional models do not accurately recapitulate the spectrum of GBM cellular states, hindering elucidation of the underlying transcriptional regulation of these states. Using our glioblastoma cerebral organoid model, we profiled the chromatin accessibility of 28,040 single cells in five patient-derived glioma stem cell lines. Integration of paired epigenomes and transcriptomes within the context of tumor-normal host cell interactions was used to probe the gene-regulatory networks underlying individual GBM cellular states in a way not readily possible in other in vitro models. These analyses identified the epigenetic underpinnings of GBM cellular states and characterized dynamic chromatin changes reminiscent of early neural development that underlie GBM cell state transitions. Despite large differences between tumors, a shared cellular compartment made up of neural progenitor-like cells and outer radial glia-like cells was observed. Together, these results shed light on the transcriptional regulation program in GBM and offer novel therapeutic targets across a broad range of genetically heterogenous GBMs. SIGNIFICANCE: Single-cell analyses elucidate the chromatin landscape and transcriptional regulation of glioblastoma cellular states and identify a radial glia-like population, providing potential targets to disrupt cell states and improve therapeutic efficacy.

Efficacy of Perioperative Intravenous Dexamethasone on Postoperative Analgesia in Scleral Buckle Surgery: A Randomized Clinical Trial.

BACKGROUND AND OBJECTIVE: Postoperative pain is frequently reported following scleral buckle (SB) surgery. This study assessed the efficacy of perioperative dexamethasone on postoperative pain and opioid use following SB. MATERIALS AND METHODS: Forty-five patients with rhegmatogenous retinal detachments undergoing SB or SB and pars plana vitrectomy were randomly assigned to either standard care of postoperative oral acetaminophen and oxycodone/acetaminophen as needed or standard care plus 8 mg single-dose peri-operative intravenous dexamethasone. A questionnaire was administered on postoperative days 0, 1, and 7 to determine visual analog scale 0 to 10 pain score and number of opioid tablets consumed. RESULTS: Mean visual analog scale score and opioid use were significantly lower in the dexamethasone group on postoperative day 0 compared with control (2.76 ± 1.96 vs 5.64 ± 3.40, P = 0.002; 0.41 ± 0.92 vs 1.34 ± 1.43, P = 0.016). The dexamethasone group also demonstrated significantly lower total opioid use (0.97 ± 1.88 vs 3.69 ± 5.32, P = 0.047). No significant differences in pain score or opioid use were observed on days 1 or 7 (P = 0.078; P = 0.311; P = 0.326; P = 0.334). CONCLUSION: Single-dose intravenous dexamethasone following SB can significantly reduce postoperative pain and opioid use. [Ophthalmic Surg Lasers Imaging Retina 2023;54:238-242.].

Concurrent immunotherapy and re-irradiation utilizing stereotactic body radiotherapy for recurrent high-grade gliomas.

BACKGROUND: Clinical trials evaluating immune checkpoint inhibition (ICI) in recurrent high-grade gliomas (rHGG) report 7%-20% 6-month progression-free survival (PFS), while re-irradiation demonstrates 28%-39% 6-month PFS. AIMS: We evaluate outcomes of patients treated with ICI and concurrent re-irradiation utilizing stereotactic body radiotherapy/fractionated stereotactic radiosurgery (SBRT) compared to ICI monotherapy. METHODS AND RESULTS: Patients ≥18-years-old with rHGG (WHO grade III and IV) receiving ICI + SBRT or ICI monotherapy between January 1, 2016 and January 1, 2019 were included. Adverse events, 6-month PFS and overall survival (OS) were assessed. Log-rank tests were used to evaluate PFS and OS. Histogram analyses of apparent diffusion coefficient maps and dynamic contrast-enhanced magnetic resonance perfusion metrics were performed. Twenty-one patients with rHGG (ICI + SBRT: 16; ICI: 5) were included. The ICI + SBRT and ICI groups received a mean 7.25 and 6.2 ICI cycles, respectively. There were five grade 1, one grade 2 and no grade 3-5 AEs in the ICI + SBRT group, and four grade 1 and no grade 2-5 AEs in the ICI group. Median PFS was 2.85 and 1 month for the ICI + SBRT and ICI groups; median OS was 7 and 6 months among ICI + SBRT and ICI groups, respectively. There were significant differences in pre and posttreatment tumor volume in the cohort (12.35 vs. 20.51; p = .03), but not between treatment groups. CONCLUSIONS: In this heavily pretreated cohort, ICI with re-irradiation utilizing SBRT was well tolerated. Prospective studies are warranted to evaluate potential therapeutic benefits to re-irradiation with ICI + SBRT in rHGG.

Using a Capsular Tension Ring (CTR) Inserter for CTR Explantation in Cases of Posteriorly Dislocated Intraocular Lens-CTR-Capsule Complex.

PURPOSE: Explantation of a dislocated capsular tension ring (CTR) from the vitreous cavity can be challenging, typically requiring a bimanual hand-shake technique or cutting the CTR into segments. We present three cases of dislocated intraocular lens (IOL)-CTR-capsule complexes in which CTRs were explanted efficiently and safely by using a CTR inserter (CTR-I) through a clear corneal incision. METHODS: Retrospective case series. RESULTS: Capsular tension rings were successfully explanted by freeing the eyelet of the CTR from the capsule, engaging it with the CTR-I hook and retracting the CTR into the device's shaft while maintaining the entire IOL-CTR-capsule complex in a safe position behind the iris plane. No complications of the procedure were observed in all three cases. All patients had subsequent uneventful IOL exchange through sutureless scleral fixation during the same surgery. CONCLUSION: The CTR inserter provides a simple and efficient approach to CTR removal from IOL-CTR-capsule complexes dislocated into the vitreous cavity. Greater awareness of this technique among providers is needed.

Reirradiation for Recurrent Glioblastoma: What We Know and What We Do Not.

The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors' suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in Journal of Clinical Oncology, to patients seen in their own clinical practice.

Noninfectious Endophthalmitis Following Intraoperative Indocyanine Green.

BACKGROUND AND OBJECTIVE: The purpose of this article is to describe a cluster of four cases of severe postoperative inflammation in eyes that received intraoperative indocyanine green (ICG) from the same lot. PATIENTS AND METHODS: This was a retrospective chart review of patients from a single-center, retina-only group practice. The ICG lot associated with the inflammatory events was identified and analyzed with high-performance liquid chromatography with UV spectroscopy. RESULTS: Four patients presented on postoperative day 1 with severe inflammation. The first patient was treated with aqueous biopsy and injection of intravitreal antibiotics, followed by topical steroid and antibiotic drops. The subsequent three patients were treated with topical steroid and antibiotic drops. All patients had resolution of inflammation by postoperative day 14 (range 10 to 14 days). High-performance liquid chromatography with UV spectroscopy failed to identify a contaminant. CONCLUSIONS: The use of intravitreal ICG dye as a surgical adjuvant may uncommonly be associated with severe postoperative inflammation. This inflammation may resolve within weeks after topical corticosteroid and antibiotic treatment. [Ophthalmic Surg Lasers Imaging Retina. 2022;53:148-151.].

MACULAR HOLE CLOSURE WITH TOPICAL STEROIDS.

BACKGROUND AND OBJECTIVE: To report the outcomes of topical difluprednate 0.05% use in the closure of full-thickness macular holes. PATIENTS AND METHODS: Retrospective chart review of 4 patients with full-thickness macular holes who received difluprednate drops 4 times daily for a minimum of 12 weeks. Main outcome measures were macular hole status assessed with optical coherence tomography, visual acuity, intraocular pressure, and complications of treatment. RESULTS: All patients had macular hole closure within 12 weeks of difluprednate exposure. Mean time to macular hole closure was 5 weeks (range, 2-12 weeks). Visual acuity improved with macular hole closure. Average baseline visual acuity was 20/42. Average visual acuity after macular hole closure was 20/26 (P = 0.14). Two patients experienced increased intraocular pressure with topical steroid use. CONCLUSION: Exposure to difluprednate in this cohort of patients with full-thickness macular holes was associated with reduced macular edema, macular hole closure, and visual improvement.