Lacrimal gland biopsies-results from a tertiary centre in the UK.

PURPOSE: To report the histopathological results of lacrimal gland biopsies over a 21-year period in a tertiary referral centre in the United Kingdom. To the best of our knowledge, this represents the largest series to be published in the United Kingdom. METHODS: A retrospective observational review was carried out for patients who underwent lacrimal gland biopsies in a tertiary referral centre at the University Hospitals of Leicester, United Kingdom between the years of 2000 and 2021. RESULTS: Lacrimal gland biopsies were performed on 248 patients during the specified 21-year period. They comprised 157 (63.3%) females and 91 (36.7%) males. The mean age at presentation was 50.8 years (range 15-94 years). The majority of patients were Caucasian (69.4%, n = 172) followed by Asians (25.0%, n = 62), African/Afro-Caribbean (4.8%, n = 12) and other ethnicities (0.8%, n = 2). The most common histopathological diagnosis was chronic inflammation dacryoadenitis (69.0%, n = 171) followed by lymphomas (15.3%, n = 38). CONCLUSION: Our study shows that chronic inflammation accounts for the majority of histopathological diagnosis followed by lymphoproliferative disorders.

Hinged tarsal flap: A novel technique for canthal tendon reconstruction.

BACKGROUND/OBJECTIVES: Reconstruction of the medial canthal region is challenging due to the complex regional anatomy. Options to reconstruct a medial canthal tendon sacrificed during tumour removal is limited. We present a novel surgical technique where hinged tarsal flap serves to substitute the canthal tendons. METHODS: This is a retrospective consecutive case series of five patients that underwent canthal reconstruction using this novel technique between May and December 2020. Electronic patient records and medical photograph database were reviewed. Patient demographics, co-morbidities, location and histology of the lesion, size of the resultant defect, reconstructive technique and post-operative complications were noted. RESULTS: All patients had good eyelid stability with no malposition, lagophthalmos or exposure keratopathy. No or minimal distraction of the eyelid from the globe, good cosmetic outcomes and no troublesome watering was reported. No wound dehiscence, no sight loss and no further surgical intervention was warranted. CONCLUSION: Multiple techniques have previously been described to reattach the medial canthal tendon with silk or supramid sutures. Transnasal wiring, stainless-steel screw and mini-plate fixation are also described, but carry a high risk of complications and are unfamiliar amongst most oculoplastic surgeons. Our technique is quick and simple and utilises autogenous tissue without breaching the periosteum which acts as a natural barrier to tumour infiltration.Refashioning the canthal tendon aids to lengthen the remaining eyelid stump, reducing the horizontal length required to reform the newly constructed eyelid and facilitates the reconstruction.

Upper eyelid reconstruction using an advancement tarso-conjunctival flap.

PURPOSE AND CONTEXT: Upper eyelid reconstruction is particularly complex due to its functional and aesthetic importance. We aim to assess the outcomes/ complications of patients who undergo upper eyelid reconstruction of the posterior lamellae with an advancing tarsonconjunctival flap from the same affected eyelid, following excision of a periocular malignancy by Mohs Micrographic Surgery. METHOD: A retrospective consecutive case note review of all eight patients who underwent the procedure between May 2016 and Jan 2021 were included. Patient demographics and factors influencing outcomes (smoking status, use of blood thinners, past medical/ drug history, size/location of the defect), follow up duration and complications were recorded. KEY RESULTS: Minor post-operative complications included an eyelid notch and retraction. There was one patient with lagophthalmos, but no exposure keratopathy. Two patients had misdirected lashes, one requiring electrolysis. Both monocular patients, who required the procedure in their only seeing eye, and were unable to tolerate a compressive dressing, had wound dehiscence. One patient was on steroids and the other on warfarin and a diabetic. No vision loss ensued and no-one underwent surgical revision. Follow up ranged from 4-52 months. CONCLUSIONS: An advancing tarso-conjunctival flap is an expedient single-stage reconstructive technique that can be used to reform up to two- thirds of the posterior lamellae in full thickness upper eyelid defects involving the lid margin. Complications are minor. It is of particular benefit in patients where occlusion of the visual axis is unacceptable, although the risk of wound dehiscence is high. This technique forms a valuable part of the systematic reconstructive algorithm.

CD4+ T helper 2 cells suppress breast cancer by inducing terminal differentiation.

Cancer immunology research is largely focused on the role of cytotoxic immune responses against advanced cancers. Herein, we demonstrate that CD4+ T helper (Th2) cells directly block spontaneous breast carcinogenesis by inducing the terminal differentiation of the cancer cells. Th2 cell immunity, stimulated by thymic stromal lymphopoietin, caused the epigenetic reprogramming of the tumor cells, activating mammary gland differentiation and suppressing epithelial-mesenchymal transition. Th2 polarization was required for this tumor antigen-specific immunity, which persisted in the absence of CD8+ T and B cells. Th2 cells directly blocked breast carcinogenesis by secreting IL-3, IL-5, and GM-CSF, which signaled to their common receptor expressed on breast tumor cells. Importantly, Th2 cell immunity permanently reverted high-grade breast tumors into low-grade, fibrocystic-like structures. Our findings reveal a critical role for CD4+ Th2 cells in immunity against breast cancer, which is mediated by terminal differentiation as a distinct effector mechanism for cancer immunoprevention and therapy.

EWSR1-ATF1 dependent 3D connectivity regulates oncogenic and differentiation programs in Clear Cell Sarcoma.

Oncogenic fusion proteins generated by chromosomal translocations play major roles in cancer. Among them, fusions between EWSR1 and transcription factors generate oncogenes with powerful chromatin regulatory activities, capable of establishing complex gene expression programs in permissive precursor cells. Here we define the epigenetic and 3D connectivity landscape of Clear Cell Sarcoma, an aggressive cancer driven by the EWSR1-ATF1 fusion gene. We find that EWSR1-ATF1 displays a distinct DNA binding pattern that requires the EWSR1 domain and promotes ATF1 retargeting to new distal sites, leading to chromatin activation and the establishment of a 3D network that controls oncogenic and differentiation signatures observed in primary CCS tumors. Conversely, EWSR1-ATF1 depletion results in a marked reconfiguration of 3D connectivity, including the emergence of regulatory circuits that promote neural crest-related developmental programs. Taken together, our study elucidates the epigenetic mechanisms utilized by EWSR1-ATF1 to establish regulatory networks in CCS, and points to precursor cells in the neural crest lineage as candidate cells of origin for these tumors.

Incidence of Clinically Significant Aniseikonia Following Encircling Scleral Buckle Surgery: An Evaluation of Refractive and Axial Length Changes Requiring Intervention.

To evaluate the incidence of symptomatic anisometropia and aniseikonia requiring intervention following surgery with combined pars plana vitrectomy (PPV) and broad 276 style encircling scleral buckle (ESB) for the repair of rhegmatogenous retinal detachments (RRD) and to report axial length (AL) and keratometry changes, a retrospective review of consecutive RRD patients treated with combined PPV and ESB between June 2016 until September 2019 was performed. All patients with symptomatic optically induced aniseikonia requiring additional interventions or surgical procedures including clear lens exchanges, secondary intraocular lens implants or contact lenses were documented. Keratometry and AL measurements were recorded for each eye and changes calculated. In total, 100 patients underwent combined PPV, ESB and endotamponade with mean age of 59.47 years (SD 11.49). AL was significantly increased (25.39 mm [SD 1.27] to 26.54 mm [SD 1.16], p = 0.0001), with a mean change of 1.15 mm (SD 0.67). Mean corneal astigmatism increased by -0.95 D (SD 0.51) in control eyes preoperatively and -1.33 (SD 0.87) postoperatively (p = 0.03). Over half of phakic patients (39/61; 64%) developed a visually significant cataract, subsequently undergoing surgery. Six of 100 patients developed symptomatic anisometropia with aniseikonia postoperatively (6%). Four proceeded with clear lens exchange despite absence of visually significant cataract (4%). Two of these initially trialled contact lenses (2%). One was intolerant, while the other decided to proceed with clear lens exchange for convenience. Only one patient (1%), being pseudophakic in both eyes, had persistent anisometropia/aniseikonia. AL and keratometry changes induced by encirclement with broad solid silicone rubber buckles are acceptable and similar to those reported previously using narrow encircling components, being unlikely to induce troublesome symptomatic anisometropia/aniseikonia. Many patients are phakic and develop visually significant cataracts, allowing correction of changes induced with the aim of visual restoration. A minority require more prolonged methods of visual rehabilitation, such as contact lens wear or clear lens exchanges. Caution and appropriate consent should be made in patients that are pseudophakic in both eyes at presentation.

The chromatin landscape of primary synovial sarcoma organoids is linked to specific epigenetic mechanisms and dependencies.

Synovial sarcoma (SyS) is an aggressive mesenchymal malignancy invariably associated with the chromosomal translocation t(X:18; p11:q11), which results in the in-frame fusion of the BAF complex gene SS18 to one of three SSX genes. Fusion of SS18 to SSX generates an aberrant transcriptional regulator, which, in permissive cells, drives tumor development by initiating major chromatin remodeling events that disrupt the balance between BAF-mediated gene activation and polycomb-dependent repression. Here, we developed SyS organoids and performed genome-wide epigenomic profiling of these models and mesenchymal precursors to define SyS-specific chromatin remodeling mechanisms and dependencies. We show that SS18-SSX induces broad BAF domains at its binding sites, which oppose polycomb repressor complex (PRC) 2 activity, while facilitating recruitment of a non-canonical (nc)PRC1 variant. Along with the uncoupling of polycomb complexes, we observed H3K27me3 eviction, H2AK119ub deposition and the establishment of de novo active regulatory elements that drive SyS identity. These alterations are completely reversible upon SS18-SSX depletion and are associated with vulnerability to USP7 loss, a core member of ncPRC1.1. Using the power of primary tumor organoids, our work helps define the mechanisms of epigenetic dysregulation on which SyS cells are dependent.

A Unique Presentation of Cutaneous Diffuse Large B-Cell Lymphoma.

Cutaneous B-cell lymphomas (CBCL) are rare heterogeneous neoplastic diseases composing about 22.5% of all cutaneous lymphomas. These diseases can be divided into primary and secondary cutaneous variants with primary cutaneous B-cell lymphoma (PCBCL) divided into three distinct entities including primary cutaneous marginal zone lymphoma, primary cutaneous follicle center lymphoma, and primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL, LT). Secondary cutaneous diffuse large B-cell lymphoma (CDLBCL) and PCDLBCL, LT are more aggressive neoplasms compared to the aforementioned CBCL with survival rates of 37% and 50% after 5 years, respectively. CDLBCL can present as cutaneous or subcutaneous nodules, papular lesions, or indurated plaques. Here, we present a case of CDLBCL of an 88-year-old female that was mistaken for lower extremity cellulitis with phlegmon. Our patient failed two courses of antibiotic therapy as an outpatient and received a third as an inpatient before a cutaneous biopsy clinched the diagnosis.

Natural course of adult-onset vitelliform lesions in eyes with and without comorbid subretinal drusenoid deposits.

PURPOSE: Adult vitelliform lesions (AVL) are associated with age related macular degeneration (AMD) and subretinal drusenoid deposits (SRDD). We evaluated the natural course of AVL, assessing the influence of SRDD on disease progression, visual function and incidence of macular atrophy (MA) and choroidal neovascular membranes (CNVM). METHODS: A retrospective cohort study was conducted between January 2011 and March 2016. Demographic, clinical and imaging data from 26 consecutive AVL patients were analysed following case note review. Optical coherence tomography images were graded for SRDD and patients divided into those with/without SRDD. Outcomes included presenting/changes in best corrected visual acuity (BCVA) and incidence of MA/CNVM. RESULTS: Mean age was 78.6 ± 7.6 years. Mean follow-up was 51.5 ± 25.6 months. Twelve patients (46.2%) had SRDD at presentation with 3 more (11.5%) developing them. Subjects with SRDD were older (mean 81.7 ± 6.1 years vs 74.3 ± 7.6 years, p = 0.010). Mean presenting BCVA was worse in SRDD eyes (0.39 ± 0.31 logMAR vs 0.19 ± 0.18 logMAR, p = 0.017). Eight of 15 patients with SRDD (53.3%) developed incident MA or CNVM; higher than those with no SRDD (1/11, 9.1%; p = 0.036). Two patients (7.7%) developed full thickness macular holes. CONCLUSIONS: Patients with AVL and SRDD likely represent an advanced pathological stage or phenotype with worse visual outcome and higher risk of MA/CNVM. Possible overlap with AMD exists. Follow-up, counselling and provisions for early detection/treatment of complications should be made. Better classification including improved understanding of phenotypic and genetic variations with reference to comorbid diseases including AMD is required. Presence of SRDD in AVL offers a dichotomous classification, indicating risk of future MA/CNVM formation.

Immunity to commensal papillomaviruses protects against skin cancer.

Immunosuppression increases the risk of cancers that are associated with viral infection1. In particular, the risk of squamous cell carcinoma of the skin-which has been associated with beta human papillomavirus (ß-HPV) infection-is increased by more than 100-fold in immunosuppressed patients2-4. Previous studies have not established a causative role for HPVs in driving the development of skin cancer. Here we show that T cell immunity against commensal papillomaviruses suppresses skin cancer in immunocompetent hosts, and the loss of this immunity-rather than the oncogenic effect of HPVs-causes the markedly increased risk of skin cancer in immunosuppressed patients. To investigate the effects of papillomavirus on carcinogen-driven skin cancer, we colonized several strains of immunocompetent mice with mouse papillomavirus type 1 (MmuPV1)5. Mice with natural immunity against MmuPV1 after colonization and acquired immunity through the transfer of T cells from immune mice or by MmuPV1 vaccination were protected against skin carcinogenesis induced by chemicals or by ultraviolet radiation in a manner dependent on CD8+ T cells. RNA and DNA in situ hybridization probes for 25 commensal ß-HPVs revealed a significant reduction in viral activity and load in human skin cancer compared with the adjacent healthy skin, suggesting a strong immune selection against virus-positive malignant cells. Consistently, E7 peptides from ß-HPVs activated CD8+ T cells from unaffected human skin. Our findings reveal a beneficial role for commensal viruses and establish a foundation for immune-based approaches that could block the development of skin cancer by boosting immunity against the commensal HPVs present in all of our skin.

Epiretinal Membrane Surgery Outcomes in Eyes with Subretinal Drusenoid Deposits: A Case Control Study.

PURPOSE: To evaluate outcomes of epiretinal membrane (ERM) surgery in eyes with subretinal drusenoid deposits (SRDDs) and to compare them with those with isolated ERM. DESIGN: Retrospective case-control study of consecutive patients who underwent pars plana vitrectomy (PPV) with ERM peeling. PARTICIPANTS: Twenty-five patients with SRDDs on spectral-domain (SD)-OCT who underwent surgery for ERM were included in the study. From the same cohort, for each case, we selected 2 age-matched control participants (50 eyes with isolated ERM). Preoperative best-corrected visual acuity (BCVA) also was matched as closely as possible. METHODS: All participants underwent PPV and ERM peel for primary ERM. MAIN OUTCOME MEASURES: Postoperative BCVA, improvement in BCVA, preoperative and postoperative central macular thickness, surgical complications, and development of age-related macular degeneration (AMD) were recorded. RESULTS: At final examination, mean postoperative BCVA was significantly less for eyes with SRDDs (0.51 logarithm of the minimal angle of resolution [logMAR] vs. 0.21 logMAR; P = 0.0001). Eyes with SRDDs demonstrated less improvement in BCVA after ERM surgery (0.13 logMAR vs. 0.30 logMAR; P = 0.0032). Eyes with SRDDs were significantly less likely to gain 2 or more Snellen lines of BCVA after ERM surgery (28% vs. 56%; P = 0.028). Three of 25 patients (12%) undergoing ERM surgery showed worsening of Snellen BCVA by 2 lines or more. Three of 25 eyes (12%) with SRDDs demonstrated advanced AMD after surgery, compared with 0 participants in the control group (P = 0.034). CONCLUSIONS: Epiretinal membrane surgery in eyes with SRDDs is associated with less favorable visual outcomes. Fewer patients demonstrate gain in BCVA, whereas a significant number show a deleterious decline. After surgery, AMD incidence seems high and patients may have an increased risk of raised intraocular pressure. These findings require further study to establish whether this represents a causal relationship. Surgeons should be vigilant for these complications. Appropriate patient counseling during the consenting process must be made.

Cancer-Specific Retargeting of BAF Complexes by a Prion-like Domain.

Alterations in transcriptional regulators can orchestrate oncogenic gene expression programs in cancer. Here, we show that the BRG1/BRM-associated factor (BAF) chromatin remodeling complex, which is mutated in over 20% of human tumors, interacts with EWSR1, a member of a family of proteins with prion-like domains (PrLD) that are frequent partners in oncogenic fusions with transcription factors. In Ewing sarcoma, we find that the BAF complex is recruited by the EWS-FLI1 fusion protein to tumor-specific enhancers and contributes to target gene activation. This process is a neomorphic property of EWS-FLI1 compared to wild-type FLI1 and depends on tyrosine residues that are necessary for phase transitions of the EWSR1 prion-like domain. Furthermore, fusion of short fragments of EWSR1 to FLI1 is sufficient to recapitulate BAF complex retargeting and EWS-FLI1 activities. Our studies thus demonstrate that the physical properties of prion-like domains can retarget critical chromatin regulatory complexes to establish and maintain oncogenic gene expression programs.

OTX2 Activity at Distal Regulatory Elements Shapes the Chromatin Landscape of Group 3 Medulloblastoma.

Medulloblastoma is the most frequent malignant pediatric brain tumor and is divided into at least four subgroups known as WNT, SHH, Group 3, and Group 4. Here, we characterized gene regulation mechanisms in the most aggressive subtype, Group 3 tumors, through genome-wide chromatin and expression profiling. Our results show that most active distal sites in these tumors are occupied by the transcription factor OTX2. Highly active OTX2-bound enhancers are often arranged as clusters of adjacent peaks and are also bound by the transcription factor NEUROD1. These sites are responsive to OTX2 and NEUROD1 knockdown and could also be generated de novo upon ectopic OTX2 expression in primary cells, showing that OTX2 cooperates with NEUROD1 and plays a major role in maintaining and possibly establishing regulatory elements as a pioneer factor. Among OTX2 target genes, we identified the kinase NEK2, whose knockdown and pharmacologic inhibition decreased cell viability. Our studies thus show that OTX2 controls the regulatory landscape of Group 3 medulloblastoma through cooperative activity at enhancer elements and contributes to the expression of critical target genes.Significance: The gene regulation mechanisms that drive medulloblastoma are not well understood. Using chromatin profiling, we find that the transcription factor OTX2 acts as a pioneer factor and, in cooperation with NEUROD1, controls the Group 3 medulloblastoma active enhancer landscape. OTX2 itself or its target genes, including the mitotic kinase NEK2, represent attractive targets for future therapies. Cancer Discov; 7(3); 288-301. ©2017 AACR.This article is highlighted in the In This Issue feature, p. 235.