Ocular side effects of checkpoint inhibitors

The incidence and impact of ocular side effects in patients treated with checkpoint inhibitors are not clearly defined.We reviewed prospective phase III clinical trials of checkpoint inhibitors applied in lung cancer, renal cell cancer, and melanoma. Case reports of the occurrence of ocular toxicities in patients receiving immune checkpoint inhibitors were also included. Of the 35 articles corresponding to phase III clinical trials with checkpoint inhibitors, ocular toxicity was described in four. Forty-six clinical cases of ocular toxicity after therapy with checkpoint inhibitors have been reported. The most frequently described ocular toxicities are uveitis, inflammatory orbital disease, and alterations of the ocular surface. Ocular toxicity is underestimated in checkpoint inhibitors clinical trials. Early ophthalmic examination and treatment with corticosteroids may improve the visual prognosis in these patients.     

The T1799A BRAF mutation is present in iris melanoma

PURPOSE: An activating mutation in exon 15 of the BRAF gene has been found in a high proportion of cutaneous pigmented lesions, but only in one case of uveal melanoma. Iris melanoma is the least common uveal melanoma and displays a less aggressive clinical course compared with posterior uveal melanoma. To date, no study has been conducted to investigate the T1799A mutation in iris melanoma. The purpose of this study was to determine whether the T1799A BRAF mutation is present in iris melanoma. METHODS: DNA was extracted from 19 archival, paraffin-embedded tissue sections of iris melanomas. Nested PCR was used to amplify exon 15 of the BRAF gene, and the product was purified, cloned into a sequencing vector, and sequenced. The sequences obtained were compared with the wild-type sequence of the BRAF gene. The presence or absence of the BRAF mutation was also compared with the clinicopathological features. RESULTS: The T1799A mutation was identified by sequencing in 9 of 19 iris melanomas. Six of the 9 cases with the BRAF mutation were recurrent tumors. All other tumors were resections for primary tumors. There was a statistically significant association between the BRAF mutation and recurrent tumor (P = 0.003). There was no association between the presence of the BRAF mutation and other clinicopathological characteristics. CONCLUSIONS: In this small study, the T1799A BRAF mutation was identified in almost half of the iris melanoma tissues samples examined. This finding suggests that there may be genetic as well as clinical differences between iris and posterior uveal melanomas.     

脉络膜黑色素瘤的治疗进展

脉络膜黑色素瘤（choroidal melanoma,CM）是成年人眼球最常见的眼内恶性肿瘤。CM恶性程度高、发生转移早、预后差,早期诊断及选择合理治疗方式对改善患者的预后至关重要。近年来,眼球摘除术作为治疗CM的传统方法已受到挑战。针对不同部位和大小的肿瘤及患者具体情况采取不同的疗法或联合治疗已成为CM的治疗原则。本文就CM的治疗进展进行综述,为降低转移率和死亡率提供相关依据。     

Use of interferon alpha 2b to manage conjunctival primary acquired melanosis and conjunctival melanoma

Primary acquired melanosis (PAM) is acquired conjunctival pigmentation that can give rise to conjunctival melanoma (CM), a malignant tumor of the bulbar and palpebral conjunctiva or the caruncle. Surgical excision is the treatment of choice for this neoplasm. Topical chemotherapy is also used for patients with PAM with atypia or CM and, in patients with recurrent or extensive disease, this may be an important option. Of the several chemotherapeutic drugs used, topical interferon alpha 2b (IFN-α2b) has become popular because of its low toxicity. Clinical evidence from case reports and case series supports the efficacy of IFN-α2b as the preferred adjuvant treatment for PAM and CM. In addition, topical IFN-α2b has been successfully applied to melanocytic tumors refractory to other treatments, such as cryotherapy and topical mitomycin C. In patients with locally advanced CM, the combination of IFN-α2b and systemic immunotherapy may serve as an alternative to exenteration. Given the low frequency of CM, long-term multicenter studies are needed to demonstrate the efficacy of IFN-α2b for preventing local recurrence and distant metastasis.     

New features in MEK retinopathy

Background

The use of molecularly targeted therapy is becoming widespread in oncology. These agents cause tumour-specific genetic alterations in signal transduction pathways, hence less generalised toxicity. Dabrafenib, a BRAF inhibitor and Trametinib, a MEK inhibitor are two molecularly targeted agents recently approved for treatment of advanced, unresectable melanomas. MEK retinopathy is a recently introduced term describing retinal toxicity secondary to MEK inhibitors.

Case presentation

A 71-year-old man presented with ‘circular, green patches’ in his central vision for 2 weeks. He had multiple relapsed stage IV BRAF gene mutant malignant melanoma. He was on treatment with Dabrafenib (Tafinlar) for 7 months and Trametinib (Mekinist) for 4 months respectively. The fundus looked normal. The OCT scan showed bilateral symmetrical cystoid macular edema, intraretinal and subretinal fluid, thickening of elliposoid zone and subretinal granular deposits. The symptoms resolved with temporary cessation of chemotherapy but OCT signs persisted.

Conclusion

This case report identifies two new remarkable features of MEK retinopathy as thickening of ellipsoid zone and ‘starry sky’ pattern of distribution of subretinal granular deposits. These changes signify photoreceptors/ RPE toxicity and dysfunction. The subretinal granular deposits showed increased autofluorescence suggested abnormal lipofuscin clearance due to RPE dysfunction. The molecularly targeted therapy has revolutionized the cancer treatment and increased the survival rate. These agents are relatively new and recently approved for clinical use and most of them are associated with ocular toxicities. Awareness of ocular symptoms, side-effect profile of drugs, monitoring regime and liaison between oncologist and eye care professional with ocular imaging is key to early diagnosis and management of ocular adverse events.

     

脉络膜黑色素瘤治疗新进展

脉络膜黑色素瘤是成人常见的原发性眼内恶性肿瘤。在白人中最常见,通常发生于单眼,其发病率增长迅速,生存率低,因此其临床研究受到广泛重视。近年来,单纯手术摘除患眼作为治疗脉络膜黑色素瘤的传统方法已受到挑战。针对不同患者,不同部位和大小的肿瘤而采取不同的治疗方法或综合治疗是一发展趋势。如保留眼球和视力的定期观察,局部切除,放射治疗,光凝治疗,生物治疗,以及多种方法的联合治疗受到重视。     

Gene therapy in ocular diseases

Gene therapy is a novel form of drug delivery that enlists the synthetic machinery of the patient's cells to produce a therapeutic agent. Genes may be delivered into cells in vitro or in vivo utilising viral or non-viral vectors. Recent technical advances have led to the demonstration of the molecular basis of various ocular diseases. Ocular disorders with the greatest potential for benefit of gene therapy include hereditary diseases such as retinitis pigmentosa, tumours such as retinoblastoma or melanoma, and acquired proliferative and neovascular retinal disorders. Gene transfer into ocular tissues has been demonstrated with growing functional success and may develop into a new therapeutic tool for clinical ophthalmology in future.     

BRAF mutations in conjunctival melanoma

PURPOSE: An activating mutation in exon 15 of the BRAF gene has been found in a high proportion of cutaneous melanomas and cutaneous nevi but not in uveal melanoma. Conjunctival melanoma shows greater clinical similarity to cutaneous melanoma than does uveal melanoma. The purpose of this study was to determine whether the T1799A BRAF mutation found in cutaneous melanoma is also present in conjunctival melanoma. METHODS: DNA was extracted from paraffin sections obtained from glutaraldehyde or formalin-fixed, paraffin-embedded conjunctival melanomas. Forty-two specimens were identified from 25 patients. Seminested PCR was used to amplify exon 15 of the BRAF gene, and the resultant PCR product was purified and directly sequenced. Sequences from conjunctival melanomas were compared with the wild-type sequence of the BRAF gene. The presence or absence of the BRAF mutation was compared with the clinicopathological features. RESULTS: The T1799A (V600E) mutation was detected by sequencing in melanomas from 5 of 22 patients as well as in the positive control, a cutaneous melanoma cell line. In this small series, no statistically significant associations between the presence of the BRAF mutation and clinicopathological characteristics were detected, although tumors with this mutation tended to have a larger diameter and greater depth of invasion and to contain epithelioid cells. CONCLUSIONS: Others have demonstrated a BRAF T1799A-activating mutation in cutaneous but not uveal melanoma. In this study, this BRAF mutation was demonstrated in some conjunctival melanoma tissue samples, suggesting that some conjunctival melanomas may share biological features in common with cutaneous melanoma.     

Uveitis in Patients Treated with CTLA-4 and PD-1 Checkpoint Blockade Inhibition

ABSTRACT

Purpose: To investigate the link between treatment with CTLA-4 and PD-1 checkpoint blockade inhibitors and the development of noninfectious uveitis.

Methods: A survey was distributed to uveitis specialists to identify patients who developed uveitis while receiving either PD-1 inhibitors pembrolizumab and nivolumab; PD-L1 inhibitors atezolizumab, avelumab, and durvalumab; or the CTLA-4 inhibitor ipilimumab.

Results: Fifteen patients from seven institutions were identified. The most common cancer diagnosis (13/15) was malignant melanoma. Fourteen patients had a new uveitis diagnosis following checkpoint blockade administration (six anterior uveitis, six panuveitis, one posterior uveitis, one anterior/intermediate combined); one patient developed optic neuritis. Uveitis was diagnosed within 6 months after drug initiation for 11/12 patients (median 63 days). Corticosteroid treatment was effective for most patients, although two patients had permanent loss of vision.

Conclusions: Patients on checkpoint inhibitor therapy should be educated to seek care if they develop ocular symptoms, and prompt referral to specialists should be incorporated into oncology protocols.     

抗PD-1/PD-L1单抗导致药物源性葡萄膜炎的研究进展

随着免疫检查点抑制剂(ICIs)在临床上治疗肿瘤的使用率越来越高,ICIs已成为治疗恶性转移性肿瘤的常用药物,为晚期肿瘤患者提供了更多的治疗选择和生存机会。目前,使用最广泛的ICIs是抗程序性细胞死亡受体-1(PD-1)/程序性细胞死亡配体-1(PD-L1)单抗类药物,而这些药物的免疫相关不良事件(irAEs)被频繁报道,它对人体多种器官均有副作用,包括消化系统、皮肤、肺、内分泌腺和眼。其中,葡萄膜炎是眼部最常见的副作用,主要表现为眼红、眼痛、畏光、流泪和视力模糊,如果能及时诊断并干预,病情会得到很好的控制,否则,此类药物源性葡萄膜炎可能导致患者严重的视力损伤和生活质量的下降。因此,ICIs眼部副作用的早期诊断至关重要,故本文就抗PD-1/PD-L1单抗导致药物源性葡萄膜炎的研究现状进行综述。     

Immune checkpoint inhibitor-associated ophthalmic adverse events: current understanding of its mechanisms, diagnosis, and management

Immune checkpoint inhibitors (ICIs) targeting cytotoxic T-lymphocyte antigen 4 and programmed cell death protein 1 receptor/ligand have revolutionized cancer treatment, achieving unprecedented efficacy in numerous malignancies. Despite the excellent therapeutic effects of ICIs, medications, such as pembrolizumab, ipilimumab, nivolumab, atezolizumab, avelumab, and durvalumab, typically cause a broad spectrum of toxicity events termed as immune-related adverse events (irAEs). Out of all irAEs, ophthalmic adverse events occur infrequently and are not comprehensively recognized. The current understanding of ophthalmic irAEs is mainly derived from case reports and case series. In this review, based on relevant articles in the literature and current evidence, we summarize the incidences, manifestations, diagnoses, underlying mechanisms, treatments, and outcomes of ophthalmic irAEs and discuss possible management strategies. A better understanding of these features is critical for managing patients with ICI-associated ophthalmic adverse events.     

Mesenchymal stem cells and potential applications in treating ocular disease

Mesenchymal stem cells (MSCs) are remarkable in stem cell biology. Not only do they have significant tissue regeneration potential, but more recently their paracrine effects (either innate or through genetic augmentation) have become increasingly recognized as useful therapeutic approaches. In particular, clinical roles for MSC therapy in neuroprotection and immune suppression are likely to emerge. These therapeutic effects will be particularly advantageous in work on neurological tissues, because MSC-based molecular therapy could overcome some of the difficulties of long-term drug delivery to tissues, such as the eye, which are relatively inaccessible to systemic delivery (for example due to the blood retina barrier). MSC therapy is, therefore, poised for significant impact in ocular molecular therapeutics, particularly for chronic diseases, such as retinal degeneration, glaucoma, and uveitis. Other molecular and tissue regeneration effects of MSCs are also likely to have impact in the management of ocular surface disease and oculoplastics.     

Uveal melanoma: Towards a molecular understanding

Uveal melanoma is an aggressive malignancy that originates from melanocytes in the eye. Even if the primary tumor has been successfully treated with radiation or surgery, up to half of all UM patients will eventually develop metastatic disease. Despite the common origin from neural crest-derived cells, uveal and cutaneous melanoma have few overlapping genetic signatures and uveal melanoma has been shown to have a lower mutational burden. As a consequence, many therapies that have proven effective in cutaneous melanoma -such as immunotherapy- have little or no success in uveal melanoma. Several independent studies have recently identified the underlying genetic aberrancies in uveal melanoma, which allow improved tumor classification and prognostication of metastatic disease. In most cases, activating mutations in the Gα11/Q pathway drive uveal melanoma oncogenesis, whereas mutations in the BAP1, SF3B1 or EIF1AX genes predict progression towards metastasis. Intriguingly, the composition of chromosomal anomalies of chromosome 3, 6 and 8, shown to correlate with an adverse outcome, are distinctive in the BAP1^mut, SF3B1^mut and EIF1AX^mut uveal melanoma subtypes. Expression profiling and epigenetic studies underline this subdivision in high-, intermediate-, or low-metastatic risk subgroups and suggest a different approach in the future towards prevention and/or treatment based on the specific mutation present in the tumor of the patients. In this review we discuss the current knowledge of the underlying genetic events that lead to uveal melanoma, their implication for the disease course and prognosis, as well as the therapeutic possibilities that arise from targeting these different aberrant pathways.     

结膜黑色素瘤的研究进展

结膜黑色素瘤（conjunctival melanoma,CM）是一种罕见的肿瘤,其相关死亡率为30%,在结膜恶性肿瘤中预后最差。CM由结膜上皮基底层的黑色素细胞恶变而来,在此之前可见相应结膜的色素性病变如原发性获得性黑变病及结膜色素痣,最常见于球结膜或角巩膜缘,也可出现于睑结膜。CM能向眼球或眼眶侵袭,并可向局部淋巴结、脑及其他器官转移。组织病理学检查为诊断本病的金标准。多数CM可通过手术切除,术后联合辅助治疗可降低局部复发及远处转移的风险。（国际眼科纵览,2020,  45：386-392）     

免疫检查点抑制剂相关眼部毒性:全球文献病例统计分析

免疫检查点抑制剂通过抑制细胞毒性T淋巴细胞相关抗原-4、程序性死亡受体-1、程序性死亡配体-1阻断肿瘤的免疫逃逸途径,从而达到杀伤肿瘤细胞的目的.然而,免疫系统的激活也会引起免疫相关的不良反应.尽管免疫检查点抑制剂所导致的眼部毒性并不常见,但是能够涉及到眼部所有组织,可能影响部分患者的免疫检查点抑制剂的使用疗程.本文通...     

LCA2型基因治疗临床试验研究进展

Leber先天性黑矇(Leber''s congenital amaurosis,LCA)是一种遗传性致盲性眼病,在婴儿早期出现严重的视力低下或丧失丧失。该疾病的LCA2型与RPE65的突变相关。既往对于LCA2在内的遗传性视网膜疾病无有效治疗方法。近年来,随着基因治疗技术的进步,遗传性视网膜疾病的治疗进展取得了巨大进步,其中最成功的便是LCA2的基因治疗。本文简要介绍了LCA2基因治疗的发展,并对既往LCA2临床试验中的注射剂型、剂量、注射方式、测量方法、治疗效果与年龄的相关性和治疗效果的稳定性进行综述,为LCA2基因治疗进入我国临床工作提供参考及临床治疗经验。     

Entwicklung einer serösen Retinopathie unter Behandlung eines metastasierten kutanen Melanoms

Inhibitors of the mitogen-activated protein kinase (MAPK) signal pathway have decisively improved the prognosis of metastatic cutaneous melanoma in patients with an activating mutation in position V600 of the BRAF gene. We report on a patient who was regularly examined in our clinic while participating in a randomized blinded clinical trial. The aim of this trial was to examine the effectiveness and tolerability of a combination of the BRAF inhibitor dabrafenib and the MAPK kinase (MEK) inhibitor trametinib compared with a monotherapy with dabrafenib (plus placebo). During therapy the patient developed a diffuse neuroretinal detachment which could not be completely reversed after discontinuation of the study medication.     

抑癌基因PTEN在脉络膜黑色素瘤中的表达

目的 通过对脉络膜黑色素瘤（choroidal melanoma,CM）以及不同组织病理分类的CM中抑癌基因PTEN表达的观察,探讨CM中PTEN的表达与CM预后的关系.方法 取已经病理学证实的54例CM患者石蜡包埋的组织进行切片.采用免疫组织化学法检测抑癌基因PTEN在CM和正常眼脉络膜组织中的表达,并且观察不同的组织病理分型、不同最大基底直径、不同年龄、不同位置的CM中抑癌基因PTEN的表达.结果 CM和正常眼脉络膜组织中PTEN的表达率差异有显著性（P＜0.01）;不同的组织病理分型表达率差异有显著性（P＜0.01）;不同最大基底直径、不同年龄、不同位置的CM中抑癌基因PTEN的表达率差异无显著性（P＞0.05）.结论 CM可表达抑癌基因PTEN,表达的强弱与其病理分型有密切关系,但与患者的发病年龄、肿瘤的位置和肿瘤的最大基底直径无明显相关关系.     

Resolución de un melanoma conjuntival con interferón tópico alfa 2 b en un paciente con intolerancia a la mitomicina C

Objective

To describe the clinical and histological resolution of a case of an inexcisable conjunctival melanoma using topical interferon alpha 2 b (INFα2b) in a patient with mitomycin C (MMC) intolerance.

Ocular surface disease associated with immune checkpoint inhibitor therapy

Immune-related adverse events (irAEs) is a term used to describe the various toxicities associated with immune checkpoint inhibitor (ICI) use. As this class of cancer immunotherapy grows, the diversity of documented irAEs also continues to expand. Ocular toxicities secondary to ICI use are relatively rare, with dry eye and uveitis as the most frequently reported ocular side effects. This article specifically investigates the relationship between ocular surface disease and ICI therapy through a review of the existing literature. Dry eye disease (DED), conjunctivitis, and keratitis were the most commonly reported irAEs affecting the ocular surface across the 29 studies reviewed. Keratoplasty graft rejection was also described in two case reports. Our review of eight clinical trials found the incidence of DED, the most common ocular surface irAE, to range from 1 to 4%. Nearly all cases of ocular surface irAEs were graded as mild or moderate in severity and were often self-limited or controlled with conservative treatment. Duration of checkpoint inhibitor use prior to onset of ocular surface side effects varied widely, ranging from days to months. Ocular surface toxicities associated with checkpoint immunotherapy appear to be under-reported and under-investigated. Further work remains to be done to investigate the full breadth of ocular surface pathologies and the molecular mechanisms by which these toxicities occur.