Submacular Hemorrhage Following Aflibercept Intravitreal Injection: A Report of Two Cases.

Anti-vascular endothelial growth factor (anti-VEGF) injections are the most effective treatment for exudative age-related macular degeneration (AMD). However, both bevacizumab and ranibizumab have been reported to cause submacular hemorrhage (SMH) in the treatment of exudative AMD. Aflibercept has also been reported to cause SMH but only in the treatment of polypoidal choroidal vasculopathy and not exudative AMD. This case series presents two patients with exudative AMD who developed SMH after treatment with aflibercept injections. The first patient is an 84-year-old female with exudative AMD in both eyes who presented with SMH four days after an aflibercept injection in her right eye. The second patient is a 77-year-old female who presented with exudative AMD in her left eye and SMH one month following an aflibercept injection. This case series shows that SMH in patients treated for exudative AMD is a rare yet possible complication of aflibercept injection that requires further research to establish its incidence and risk factors.

Chemotherapy after immune checkpoint inhibitor failure in metastatic melanoma: a retrospective multicentre analysis.

INTRODUCTION: Despite remarkably improved outcomes with immune checkpoint inhibition, many patients with metastatic melanoma will eventually require further therapy. Chemotherapy has limited activity when used first-line but can alter the tumour microenvironment and does improve efficacy when used in combination with immunotherapy in lung cancer. Whether chemotherapy after checkpoint inhibitor failure has relevant activity in patients with metastatic melanoma is unknown. METHODS: Patients with metastatic melanoma treated with chemotherapy after progression on immunotherapy with checkpoint inhibitors were identified retrospectively from 24 melanoma centres. Objective response rate (ORR), progression-free survival (PFS), overall survival (OS) and safety were examined. RESULTS: In total, 463 patients were treated between 2007 and 2017. Fifty-six per cent had received PD-1-based therapy before chemotherapy. Chemotherapy regimens included carboplatin + paclitaxel (32%), dacarbazine (25%), temozolomide (15%), taxanes (9%, nab-paclitaxel 4%), fotemustine (6%) and others (13%). Median duration of therapy was 7.9 weeks (0-108). Responses included 0.4% complete response (CR), 12% partial response (PR), 21% stable disease (SD) and 67% progressive disease (PD). Median PFS was 2.6 months (2.2, 3.0), and median PFS in responders was 8.7 months (6.3, 16.3), respectively. Twelve-month PFS was 12% (95% CI 2-15%). In patients who had received anti-PD-1 before chemotherapy, the ORR was 11%, and median PFS was 2.5 months (2.1, 2.8). The highest activity was achieved with single-agent taxanes (N = 40), with ORR 25% and median PFS 3.9 months (2.1, 6.2). Median OS from chemotherapy start was 7.1 months (6.5, 8.0). Subsequent treatment with checkpoint inhibitors achieved a response rate of 16% with a median PFS of 19.1 months (2.0-43.1 months). No unexpected toxicities were observed. CONCLUSION: Chemotherapy has a low response rate and short PFS in patients with metastatic melanoma who have failed checkpoint inhibitor therapy, although activity varied between regimens. Chemotherapy has a limited role in the management of metastatic melanoma.

Hyperacute toxicity with combination ipilimumab and anti-PD1 immunotherapy.

BACKGROUND: Combination ipilimumab and nivolumab is approved for several malignancies. Toxicity most often occurs 6-10 weeks into treatment. Whether very early toxicity is harder to manage or influences efficacy is unknown. METHODS: Consecutive metastatic melanoma patients who developed hyperacute toxicity, defined as Grade 2+ irAE within 21 days of receiving ipilimumab + anti-PD-1 were retrospectively identified from nine centres. RESULTS: A total of 82 patients developed hyperacute toxicity (estimated incidence 9%), at a median 10 days (range 1-21). Toxicities included colitis (N = 23), rash (17), hepatitis (9), endocrine (9), pneumonitis (6) and neurotoxicity (4) and were G2 (38%), G3 (52%), G4 (6%) and G5 (2% myocarditis). Fifty-nine percent required treatment beyond oral steroids, including IV steroids (28%), infliximab and other immunosuppression (30%). A total of 29% patients developed an additional hyperacute toxicity and 26% another toxicity >21 days after treatment commencement but before further immunotherapy. The objective response rate (ORR) was 54%, and after a median 11.6 mo follow-up, median PFS was 7.4 mo. Increasing levels of immunosuppression was associated with a reduced PFS (12-month PFS 62% no immunosuppression versus 49% oral steroids versus 33% IV steroids versus 20% further immunosuppressants, p = 0.006). There was no significant difference in ORR or PFS by duration of immunosuppression. CONCLUSIONS: Hyperacute toxicities from combination immunotherapy have a wide spectrum and can be severe. Many patients require significant immunosuppression for prolonged durations and remain at risk of further severe toxicity. Melanoma outcomes in such patients appear similar to those of trial populations, although greater immunosuppression requirements may be associated with inferior outcomes.

Photodynamic Therapy for Choroidal Metastasis Tumor Control and Visual Outcomes in 58 Cases: The 2019 Burnier International Ocular Pathology Society Lecture.

PURPOSE: To determine outcomes after photodynamic therapy (PDT) for choroidal metastasis. DESIGN: Retrospective interventional case series. PARTICIPANTS: Forty-three patients with 40 eyes harboring 58 choroidal metastases. METHODS: Treatment with standard fluence PDT using verteporfin. MAIN OUTCOME MEASURES: Tumor control and visual outcomes. RESULTS: The primary cancer originated in the lung (n = 17 [39%]), breast (n = 16 [37%]), kidney (n = 3 [8%]), thyroid (n = 2 [6%]), and other sites (n = 5 [10%]). The mean patient age at entry was 61 years. Ocular symptoms included decreased visual acuity (n = 23 [53%]), visual field defect (n = 2 [5%]), floaters (n = 7 [16%]), flashes (n = 3 [7%]), and asymptomatic (n = 8 [19%]). The median entering visual acuity (Snellen equivalent) was 20/40. The median tumor diameter was 5.0 mm, and median thickness by ultrasonography was 2.0 mm. The median distance to the optic disc was 3.0 mm, and that to the foveola was 2.0 mm. Of the 43 patients, 35 maintained follow-up (40 eyes, 45 tumors), and PDT achieved tumor control with 1 session (n = 32 tumors [71%]) or 2 sessions (n = 3 tumors [7%]) and failed to achieve regression (n = 10 tumors [22%]). The 10 metastases for which treatment failed were managed further with plaque radiotherapy (n = 3), proton beam radiotherapy (n = 1), external beam radiotherapy (n = 1), systemic chemotherapy (n = 4), and observation (patient preference; n = 1). A comparison of clinical features for tumor control (PDT alone vs. PDT plus additional therapy) revealed those controlled with PDT alone were more likely to be adenocarcinoma (73% vs. 30%; P = 0.02) and those eyes were more like to achieve final visual acuity of 20/20 to 20/40 (66% vs. 30%; P = 0.03), with better median final Snellen visual acuity (20/30 vs. 20/70; not significant). Primary cancer site or ocular tumor features (size, location, color, shape, related subretinal fluid) did not impact tumor control. In the entire group of 40 eyes, visual acuity improved or remained stable in 28 (70%) and decreased in 12 (30%), related to subfoveal scar, persistent subretinal fluid, reactive exudation, radiation maculopathy, and brain metastasis. At last follow-up (mean, 20 months), of the entering 43 patients, 9 (21%) were alive and 34 (79%) had died of systemic metastasis. CONCLUSIONS: Photodynamic therapy with verteporfin is an effective outpatient method for small to medium choroidal metastatic tumors, providing tumor control in 78% of eyes and visual outcome of 20/20 to 20/40 in 66% of eyes.

Visual acuity outcomes in Coats disease by classification stage in 160 patients.

PURPOSE: To assess visual outcomes of Coats disease by classification stage. METHODS: A retrospective review was conducted on consecutive patients with Coats disease, classified according to Shields classification and with available Snellen visual acuity before and after treatment. RESULTS: There were 160 eyes with Coats disease (stage 1 (n=2) vs stage 2A (n=17) vs stage 2B (n=22) vs stage 3A1 (n=26) vs stage 3A2 (n=40) vs stage 3B (n=42) vs stage 4 (n=9) vs stage 5 (n=2)). By comparison, more advanced stage showed greater frequency of poor presenting visual acuity (<20/200) (0% vs 0% vs 50% vs 35% vs 38% vs 83% vs 100% vs 100%, p<0.001) and higher mean intraocular pressure (17 vs 15 vs 15 vs 15 vs 15 vs 15 vs 37 vs 26, p<0.001). More advanced stage was less likely managed with laser photocoagulation (100% vs 87% vs 48% vs 62% vs 74% vs 35% vs 0% vs 0%, p<0.001) and more likely with cryotherapy (0% vs 47% vs 81% vs 81% vs 82% vs 88% vs 50% vs 100%, p=0.001). More advanced stage was associated with lower frequency of visual acuity ≥20/40 (100% vs 71% vs 5% vs 42% vs 23% vs 5% vs 0% vs 0%, p<0.001) and greater frequency of visual acuity <20/200 (0% vs 12% vs 36% vs31 % vs 45% vs 88% vs 0% vs 100%, p<0.001). CONCLUSION: Visual acuity in eyes with Coats disease parallels staging with more advanced stage demonstrating poorer visual acuity at presentation and final visit.

High-resolution MRI demonstrates that more than 90% of small intracranial melanoma metastases develop in close relationship to the leptomeninges.

BACKGROUND: Despite classic teaching that intracranial metastases typically arise at the gray-white matter junction, small intracranial melanoma metastases (IMM) are frequently observed at the interface between the cortex and leptomeninges (ie, "corticomeningeal interface"), suggesting possible leptomeningeal origin. METHODS: MRI brain examinations of melanoma patients treated at a specialist oncology center from July 2015 to June 2017 were retrospectively reviewed. The MRI examination on which IMM were first visible was identified, utilizing 1 mm volumetric postcontrast imaging prior to local therapy. Individual metastases (up to 10 per patient) were assessed for the presence of leptomeningeal contact, as well as their number, size, and morphology. Lesions ≥10 mm in long axis were excluded, in order to examine early metastatic disease. RESULTS: Seventy-five patients had evidence of IMM. Fifteen patients had only lesion(s) measuring ≥10 mm at diagnosis, leaving 60 patients. One hundred ninety-two individual metastases were examined (median 2 per patient; interquartile range, 1-4), 174 (91%) demonstrating leptomeningeal contact. A nodular morphology was observed in 154 of 192 (82%), 32 (17%) were ovoid but elongated along the cortex, and 6 (3%) were linear. Only 3 patients (5%) also exhibited a "classic" linear leptomeningeal disease appearance. CONCLUSIONS: Most IMM measuring between 2 and 9 mm in diameter are corticomeningeal nodules. These data raise the hypothesis that deeper parenchymal extension of IMM occurs secondarily. If the leptomeninges provide a preferential site for establishment of IMM, further investigation of the underlying biology of this phenomenon may provide opportunities for novel therapeutic strategies for patients with IMM.

A closer look at immune-mediated myocarditis in the era of combined checkpoint blockade and targeted therapies.

Immune checkpoint inhibitors (ICI) and tyrosine kinase inhibitors (TKI) have transformed the management of many malignancies. Although rare, immune-mediated myocarditis presents unique clinical challenges due to heterogenous presentation, potential life-threatening consequences, and the time-critical need to differentiate it from other causes of cardiac dysfunction. Increasingly, TKI are being combined with ICI to promote immune modulation and improve efficacy. However, these combinations are associated with more toxicities. This series describes six patients with advanced melanoma who developed immune-mediated myocarditis while receiving an anti-PD-1 antibody or an anti-PD-L1 antibody plus a mitogen-activated protein kinase inhibitor. It provides a review of their heterogenous clinical presentations, investigational findings and treatment outcomes. Presentations ranged from asymptomatic cardiac enzyme elevation to death due to heart failure. We highlight the role of cardiac MRI (CMRI), a sensitive and non-invasive tool for the early detection and subsequent monitoring of myocardial inflammation. Five of the six patients exhibited CMRI changes characteristic of myocarditis, including mid-wall myocardial oedema and late gadolinium enhancement in a non-coronary distribution. Critically, two of these patients had normal findings on echocardiogram. Of the five patients who received immunosuppression, four recovered from myocarditis and one died of cardiac failure. The sixth patient improved with cardiac failure management alone. Three of the four patients responding to ICI derived long-term benefit. Clinical vigilance, prompt multimodal diagnosis and multidisciplinary management are paramount for the treatment of immune-mediated myocarditis.

Predictors of enucleation in Coats disease: analysis of 259 eyes of 259 patients at a single center.

PURPOSE: To evaluate the effects of clinical features associated with enucleation in eyes with Coats disease. METHODS: The medical records of all patients with Coats disease at the Ocular Oncology, Wills Eye Hospital from November 1, 1973, to July 31, 2018, were reviewed retrospectively. The clinical features pertaining to need for ultimate enucleation and time to enucleation were compared. RESULTS: The records of 351 eyes were reviewed, of which 259 had follow-up at our center and 32 (12%) were managed with enucleation. Reasons for enucleation included neovascular glaucoma (n = 24 [75%]), possible tumor (6 [19%]), and phthisis bulbi (2 [6%]). Compared to nonenucleated eyes, enucleated eyes had more extensive clock hour involvement of telangiectasia (P < 0.001), light bulb aneurysms (P < 0.001), exudation (P < 0.001), and subretinal fluid (P < 0.001). On adjusted analysis by binomial logistic regression, variables predictive of enucleation included presence of iris neovascularization (P = 0.01), ultrasonographic retinal detachment (P = 0.004), open-funnel retinal detachment (P = 0.04), closed-funnel retinal detachment (P = 0.01), ultrasonographic elevation of subretinal fluid by millimeters (P = 0.001), and angiographic extent of light bulb aneurysms by clock hours (P = 0.02). By Kaplan-Meier analysis of 4-year cumulative risk of enucleation, risk factors for enucleation included presence of iris neovascularization (hazard ratio [HR] 31.0; P < 0.001), ultrasonographic retinal detachment (HR 56.2; P < 0.001), open-funnel retinal detachment (HR 2.7; P = 0.01), and closed-funnel retinal detachment (HR 4.5; P < 0.001). CONCLUSIONS: Clinical features that predict risk of and time to enucleation in eyes with Coats disease include iris neovascularization, ultrasonographic presence and millimeter-elevation of retinal detachment, and angiographic extent of light bulb aneurysms.

Coats Disease: Clinical Features and Outcomes by Age Category in 351 Cases.

PURPOSE: To investigate features and outcomes of Coats disease by patient age. METHODS: Patients with Coats disease from 1973 to 2018 were evaluated based on age category at presentation (3 years or younger vs older than 3 to 10 years vs older than 10 years). RESULTS: There were 351 eyes of 351 patients with Coats disease diagnosed (2 vs 6 vs 27 years, P < .001). The youngest age group had more referral diagnoses of retinoblastoma (29% vs 15% vs 0%, P < .001), worse presenting visual acuity (< 20/200: 80% vs 67% vs 31%, P < .001), more advanced Coats disease stage (stage 3B: 65% vs 38% vs 10%, P < .001), and greater clock-hour extent of telangiectasia (7 vs 5 vs 4, P < .001), light bulb aneurysms (7 vs 4 vs 3, P < .001), exudation (10 vs 7 vs 5, P < .001), and subretinal fluid (10 vs 7 vs 4, P < .001). The oldest patients received a greater total number of treatments (3.3 vs 3.1 vs 4.4, P = .04), with more argon laser photocoagulation (37% vs 52% vs 73%, P < .001) and intravitreal anti-vascular endothelial growth factor (6% vs 9% vs 23%, P < .002) and less cryotherapy (74% vs 84% vs 58%, P < .001). At mean follow-up (70 vs 65 vs 38 months, P = .02), the youngest patients had poorer visual acuity outcome (< 20/200: 83% vs 64% vs 39%, P < .001), had less disease resolution (43% vs 65% vs 62%, P = .01), and were more likely to ultimately require enucleation (22% vs 10% vs 6%, P = .01). CONCLUSIONS: Younger patients (3 years or younger) with Coats disease present with worse visual acuity and more advanced disease stage, and are more likely to require ultimate enucleation. [J Pediatr Ophthalmol Strabismus. 2019;56(5):288-296.].

Pneumocystis jirovecii in a patient on dose-dense chemotherapy for early breast cancer.

A 70-year-old woman underwent adjuvant chemotherapy with dose-dense doxorubicin and cyclophosphamide for early breast cancer. After her fourth cycle of chemotherapy, she developed severe fatigue and cough with rapid-onset hypoxic respiratory failure. Investigations demonstrated extensive bilateral consolidation with positive bronchial washings for Pneumocystis jirovecii by polymerase chain reaction (PCR). Despite high-dose trimethoprim-sulfamethoxazole, she progressed to multi-organ failure and succumbed. Pneumocystis jirovecii pneumonia (PJP) has traditionally rarely occurred in women on adjuvant breast cancer chemotherapy but may pose a more serious risk in dose-dense regimes due to higher concurrent exposure to anti-emetic corticosteroids. Clinicians are alerted to the need for vigilance of this rare complication and for rationalization of dexamethasone dosage to mitigate this risk, particularly in the era of modern triple-agent anti-emetic regimens.

Factors Predictive of Subretinal Fluid Resolution in Coats Disease: Analysis of 177 Eyes in 177 Patients at a Single Center.

PURPOSE: The aim of this study was to investigate factors predictive of subretinal fluid (SRF) resolution in Coats disease. DESIGN: Retrospective cohort study. METHODS: Institutional review board-approved review of patients diagnosed with Coats disease demonstrating SRF (stage 3-5) at a single center from November 1973 to July 2018 with comparison of eyes that had resolution of SRF to those in which SRF persisted. RESULTS: There were 177 cases (154 males, 87%) of Coats disease diagnosed at a mean age of 8 years. After a mean follow-up of 62 months, SRF resolved in 110 (62%) and persisted in 67 (38%) eyes. Comparison (resolved SRF vs persistent SRF) revealed classification as stage 3A [63 (57%) vs 20 (29%)], stage 3B [47 (43%) vs 40 (60%)], or stage 4 [0 (0%) vs 7 (11%)] (P < 0.001). Eyes with resolved SRF presented with fewer clock hours of telangiectasia (mean: 5 vs 7 clock hours, P < 0.001), light bulb aneurysms (mean: 5 vs 7 clock hours, P < 0.001), exudation (mean: 7 vs 10 clock hours, P < 0.001), and extent of SRF (mean: 7 vs 10 clock hours, P < 0.001). Factors predictive of SRF resolution included absence of iris neovascularization on fluorescein angiography [odds ratio 0.05 (95% confidence interval 0.01-0.60), P = 0.02], and less elevated SRF by ultrasonography [odds ratio 0.84 (95% confidence interval 0.76-0.95), P = 0.004). For every 1-mm decrease in SRF, likelihood of SRF resolution increased by 16%. CONCLUSIONS: Resolution of SRF was achieved in the majority of eyes (62%) with stage 3 to 5 Coats disease. Predictors of SRF resolution included lack of neovascularization on fluorescein angiography and less elevation of SRF by ultrasonography.

The survivorship experience for patients with metastatic melanoma on immune checkpoint and BRAF-MEK inhibitors.

PURPOSE: Immune checkpoint inhibitors (ICI) and BRAF and MEK inhibitors (BMi) have improved survival in metastatic melanoma (MM). However, the experience of long-term responders remains undescribed. This study characterised survivorship issues faced by long-term responders to ICI or BMi. METHODS: Patients with MM, aged ≥ 18 years old, ≥ 6 months post-ICI or BMi initiation with an objective response or stable disease. A 72-question survey assessed physical and psychological effects, impact on lifestyle, access to information, satisfaction with care, and availability of supports. RESULTS: One hundred and five of 120 (88%) patients completed the survey (ICI 69/BMI 36). For the ICI cohort, 39 (57%) were receiving ongoing treatment, 17 ceased due to toxicity and 13 due to a sustained response. For the BMi cohort, 31 (85%) were receiving ongoing treatment, 4 ceased due to toxicity and 1 due to a sustained complete response. At data cut-off on 18 December 2018, median PFS (range) was 2.5 years (1.3-8.5) for ICI and 3.1 years (0.6-7.3) for BMi. Long-term toxicities included dry/itchy skin (ICI 51, 74%/ BMi 25, 69%), arthralgias (ICI 30, 58%/ BMi 23, 64%) and fatigue (ICI 62, 90%/ BMi 33, 92%). Psychological morbidity was common, including anxiety awaiting results (ICI 50, 72%/ BMi 29, 81%), fear of melanoma recurring or progressing (ICI 56, 81%/ BMi 31, 86%) or death (ICI 44, 64%/ BMi 26, 72%). CONCLUSION: MM survivors experience chronic treatment toxicities and frequently report psychological concerns. IMPLICATIONS FOR CANCER SURVIVORS: Survivors may benefit from discussions regarding long-term toxicities and tailored psychological supports.

Coats disease in 351 eyes: Analysis of features and outcomes over 45 years (by decade) at a single center.

Purpose: To assess features and outcomes of Coats disease over 5-decades. Methods: Retrospective review of Coats disease patients at a single center. Features and outcomes were compared based on decade of presentation. Results: There were 351 patients with Coats disease. The presenting median age (6 years), male sex (84%), and unilaterality (100%) did not change per decade. Coats disease classification did not change per decade with Stage 1 (1%), Stage 2 (21%), Stage 3 (68%), Stage 4 (6%), and Stage 5 (1%). Clinical features that changed per decade (1970s vs. 1980s vs. 1990s vs. 2000s vs. 2010s) included 1980s features of more eyes with exudation in all 4 quadrants (22% vs. 58% vs. 44% vs. 33% vs. 27, P = 0.01) and total exudative retinal detachment (33% vs. 53% vs. 39% vs. 27% vs. 21%, P < 0.001). Imaging features that changed per decade included 2010s greater fluorescein angiographic extent of retinal non-perfusion in mean clock hours (4 vs. 4 vs. 3 vs. 5 vs. 6, P = 0.003), and 1980s greater mean height of retinal detachment ultrasonographically (5 vs. 12 vs. 5 vs. 5 vs. 4 mm, P < 0.001). Treatment features that changed per decade included 1980s greater primary enucleation (11% vs. 16% vs. 3% vs. 4% vs. 1%, P = 0.001), and 2010s greater use of laser photocoagulation (55% vs. 33% vs. 38% vs. 40% vs. 72%, P < 0.001), sub-Tenon corticosteroid (0% vs. 4% vs. 5% vs. 8% vs. 29%, P < 0.001), and intravitreal anti-VEGF) (0% vs. 4% vs. 2% vs. 13% vs. 18%, P = 0.003). Outcomes that changed per decade included 2010s findings of more complete resolution of subretinal fluid (64% vs. 59% vs. 38% vs. 58% vs. 72%, P = 0.01) and less need for primary/secondary enucleation (17% vs. 27% vs. 14% vs. 13% vs. 6%, P = 0.04). Conclusion: Eyes with Coats disease in the 1980s demonstrated more advanced findings, often requiring enucleation. Over the decades, greater use of laser photocoagulation and injections has led to improved disease resolution with greater globe salvage.

Profound MEK inhibitor response in a cutaneous melanoma harboring a GOLGA4-RAF1 fusion.

BRAF and CRAF are critical components of the MAPK signaling pathway which is activated in many cancer types. In approximately 1% of melanomas, BRAF or CRAF are activated through structural arrangements. We describe here a metastatic melanoma with a GOLGA4-RAF1 fusion and pathogenic variants in CTNNB1 and CDKN2A. Anti-CTLA4/anti-PD1 combination immunotherapy failed to control tumor progression. In the absence of other actionable variants the patient was administered MEK inhibitor therapy on the basis of its potential action against RAF1 fusions. This resulted in a profound and clinically significant response. We demonstrated that GOLGA4-RAF1 expression was associated with ERK activation, elevated expression of the RAS/RAF downstream co-effector ETV5, and a high Ki67 index. These findings provide a rationale for the dramatic response to targeted therapy. This study shows that thorough molecular characterization of treatment-resistant cancers can identify therapeutic targets and personalize management, leading to improved patient outcomes.

Rheumatic immune-related adverse events secondary to anti-programmed death-1 antibodies and preliminary analysis on the impact of corticosteroids on anti-tumour response: A case series.

IMPORTANCE: Rheumatic immune-related adverse events (irAEs) occur in approximately 10-20% of anti-programmed death 1 (anti-PD1)-treated cancer patients. There are limited data on the natural history, optimal treatment and long-term oncological outcomes of patients with rheumatic irAEs. OBJECTIVE: The objective of the study was to describe the spectrum and natural history of rheumatic irAEs and the potential impact of rheumatic irAEs and immunomodulators on anti-PD1 tumour efficacy. METHODS: Cancer patients with pre-existing rheumatic disease before anti-PD1 therapy or de novo rheumatic irAEs on anti-PD1 therapy were retrospectively reviewed across three sites. Patient demographics, treatment history, anti-PD1 irAEs, and anti-PD1 responses were evaluated. Relationships between the development or pre-existence of rheumatic irAE, use of immunomodulatory agents and outcomes were evaluated. RESULTS: This multicenter case series describes 36 cancer patients who had rheumatic disease before anti-PD1 therapy (n = 12) or developed de novo rheumatic irAEs (n = 24). Thirty-four of the 36 patients sustained rheumatic irAEs (median time to rheumatic irAE: 14.5 weeks), including 24 de novo (18 inflammatory arthritis, three myositis, two polymyalgia rheumatica, one fasciitis) and 10 flares in 12 patients with pre-existing rheumatic disease. Corticosteroids were used in 30 of 36 patients (median duration: 10 months), and disease-modifying antirheumatic drugs were used in 14 of 36 patients (median duration: 5.5 months). The objective response rate to anti-PD1 therapy was 69% (n = 25/36) overall and 81% (n = 21/26) in the melanoma subgroup. CONCLUSIONS: Rheumatic irAEs are often chronic and require prolonged immunomodulatory therapy. Prospective studies are required to define optimal management of rheumatic irAEs that maintain long-term anticancer outcomes.

Anti-PD-1/PD-L1 immunotherapy in patients with solid organ transplant, HIV or hepatitis B/C infection.

BACKGROUND: Anti-programmed cell death protein 1/programmed death ligand 1 (PD-1/PD-L1) immunotherapy is now routinely used to treat several cancers. Clinical trials have excluded several populations, including patients with solid organ transplant, HIV infection and hepatitis B/C infection. We examined the safety outcomes of these populations treated with anti-PD-1/PD-L1 treatment in a multicentre retrospective study. METHODS: Patients from 16 centres with advanced cancer and solid organ transplant, HIV infection or hepatitis B/C infection were included. Demographic, tumour, treatment, toxicity and outcome data were recorded. RESULTS: Forty-six patients were included for analysis, with a median age of 60 years, and the majority of patients diagnosed with melanoma (72%). Among six patients with solid organ transplants, two graft rejections occurred, with one resulting in death, whereas two patients achieved partial responses. There were four responses in 12 patients with HIV infection. In 14 patients with hepatitis B, there were three responses, and similarly, there were three responses in 14 patients with hepatitis C. There was no unexpected toxicity in any viral infection group or an increase in viral load. CONCLUSION: Patients with HIV or hepatitis B/C infections treated with anti-PD-1/PD-L1 immunotherapy may respond to treatment without increased toxicity. Given the risk of graft rejection in solid organ transplant patients and also the potential for response, the role of anti-PD-1/PD-L1 immunotherapy needs to be carefully considered.

Clinical and genetic investigation of amantadine-associated corneal edema.

PURPOSE: Amantadine use has been temporally associated with bilateral corneal edema in a series of cases; however, its pathophysiological mechanisms have yet to be elucidated. We sought to rule out subclinical Fuchs dystrophy as a contributor, characterize its pattern of corneal edema, and describe the long-term outcome of concurrent topical steroids while resuming amantadine. PATIENT AND METHODS: After a 44-year-old woman presented with new acute onset bilateral corneal edema, amantadine was discontinued, with clinical improvement. However, neurological decompensation required restarting amantadine, which she did concurrently with topical loteprednol. To determine whether subclinical Fuchs dystrophy might be present, triplet-primed polymerase chain reaction was conducted to measure copy number of the CTG18.1 trinucleotide repeat in TCF4. Specular microscopy and Scheimpflug imaging were conducted and followed for 32 months to assess for resolution and stability. Literature review was conducted to assess for consistency of the clinical phenotype. RESULTS: Corneal edema resolved clinically 4 weeks after discontinuation of amantadine. Serial Scheimpflug imaging demonstrated resolution of posterior and central corneal edema and specular microscopy revealed intracellular opacities with loss of endothelial cell density. Despite resuming amantadine, Scheimpflug imaging and specular microscopy measurements remained stable at 32 months. Triplet-primed PCR of CTG18.1 in TCF4 revealed no trinucleotide repeat expansion. CONCLUSIONS: Amantadine-associated corneal edema is characteristically posterior and central and appears unlikely to represent early or subclinical decompensation of Fuchs dystrophy. We describe the unique outcome of continued corneal clearance after restarting amantadine concurrently with steroids, a pattern that has persisted over 32 months to date.

INTRAARTERIAL CHEMOTHERAPY FOR RETINOBLASTOMA IN A 2-MONTH-OLD INFANT.

PURPOSE: Intraarterial chemotherapy for retinoblastoma is usually reserved for infants aged 3 months or older because of the intricacy of the newborn vascular anatomy making the procedure technically challenging. The authors report a successful case of intraarterial chemotherapy performed in a 2-month-old infant using a minimal exposure approach. METHODS: Case report. RESULTS: A 2-month-old infant presented with leukocoria and was subsequently diagnosed with an exophytic Group D retinoblastoma in the right eye. The infant received melphalan 3 mg delivered into the ostium of the ophthalmic artery of the right eye under fluoroscopic guidance. Examination under anesthesia a month later showed complete tumor regression to a calcified Type I scar. After a second cycle of intraarterial chemotherapy, no further treatment was necessary. There were no complications. CONCLUSION: Intraarterial chemotherapy is generally used for retinoblastoma in infants aged 3 months or older. The patient was successfully catheterized and treated at 2 months of age, with complete tumor regression after a single chemotherapy dose. Thus, in expert hands, intraarterial chemotherapy can be considered in such young infants.