Biallelic and monoallelic variants in EFEMP1 can cause a severe and distinct subtype of heritable connective tissue disorder.

Variants in EFEMP1, encoding Fibulin-3, were previously reported as a rare cause of heritable connective tissue disorder (HCTD) with recurrent hernias and joint hypermobility. We report three new cases with biallelic or monoallelic EFEMP1 variants and severe hernia phenotypes. Two male siblings of 10 and 13 years old presented with marfanoid habitus, recurrent inguinal and umbilical hernias, generalized joint hypermobility, and scoliosis. Parents and halfsiblings reported joint hypermobility and umbilical hernias. The eldest boy died at age 16 from incarcerated gastrointestinal herniation complicated by gastric and bowel necrosis with perforation. Autopsy revealed widespread intestinal diverticula. Immunohistochemistry of skin and fascia tissue did not reveal any abnormalities, including normal staining of elastic fibers. Both siblings harbored compound heterozygous likely pathogenic EFEMP1 variants (c.1320 + 2T > A, p.? and c.698G > A, p.Gly233Asp). An unrelated 58-year-old male had marfanoid features, high myopia, recurrent diaphragmatic and inguinal hernias, and chronic gastrointestinal dilatation with severe malabsorption. Both his dizygotic twin-brother and mother had recurrent hernias and high myopia. This man died at 59 years of age, and autopsy showed extensive diaphragmatic herniation, bowel diverticula, and pulmonary emphysema. A heterozygous EFEMP1 splice-variant (c.81 + 1G > A, p.?) was identified, causing exon skipping leading to a start-loss. Targeted genome reanalysis nor RNA-sequencing revealed a second variant at the other allele. The reported individuals expand the clinical and pathological phenotypes of EFEMP1-related disease, a distinct entity within the spectrum of HCTD. The severe and recurrent hernias, gastrointestinal dilatation, and diverticulosis result in an increased risk for life-threatening complications, demanding early recognition and close monitoring.

Histological evidence of MAPK pathway activation across subtypes of adult orbital xanthogranulomatous disease irrespective of the detection of oncogenic mutations.

Adult orbital xanthogranulomatous disease (AOXGD) is a spectrum of histiocytoses with four subtypes. Mitogen-activated protein kinase (MAPK) pathway mutations have been detected in various histiocytic neoplasms, little is known about this in AOXGD. Targeted regions of cancer- and histiocytosis-related genes were analyzed and immunohistochemical staining of phosphorylated ERK (pERK), cyclin D1 and PU.1 was performed in 28 AOXGD and 10 control xanthelasma biopsies to assess MAPK pathway activation. Mutations were detected in 7/28 (25%) patients. Positive staining for pERK and/or cyclin D1 was found across all subtypes in 17/27 (63%) patients of whom 12/17 (71%) did not harbour a mutation. Xanthelasma tissue stained negative for pERK and cyclin D1. Relapse occurred in 5/7 (71%) patients with a MAPK pathway mutation compared to 8/21 (38%) patients in whom no mutation could be detected. Molecular analysis and evaluation for systemic disease is warranted to identify patients at risk of recurrent xanthomatous disease.

Diagnostics and treatment delay in primary central nervous system lymphoma: What the neurosurgeon should know.

PURPOSE: The gold standard for diagnostics in primary central nervous system lymphoma (PCNSL) is histopathological diagnosis after stereotactic biopsy. Yet, PCNSL has a multidisciplinary diagnostic work up, which associated with diagnostic delay and could result in treatment delay. This article offers recommendations to neurosurgeons involved in clinical decision-making regarding (novel) diagnostics and care for patients with PCNSL with the aim to improve uniformity and timeliness of the diagnostic process for patients with PCNSL. METHODS: We present a mini review to discuss the role of stereotactic biopsy in the context of novel developments in diagnostics for PCNSL, as well as the role for cytoreductive surgery. RESULTS: Cerebrospinal fluid-based diagnostics are supplementary and cannot replace stereotactic biopsy-based diagnostics. CONCLUSION: Histopathological diagnosis after stereotactic biopsy of the brain remains the gold standard for diagnosis. Additional diagnostics should not be a cause of diagnostic delay. There is currently no sufficient evidence supporting cytoreductive surgery in PCNSL, with recent studies showing contradictive data and suboptimal study designs.

Adult orbital xanthogranuloma: long-term follow-up of treated cases.

BACKGROUND: Adult orbital xanthogranulomatous disease (AOXGD) is a group of rare disorders. Four subtypes are identified: adult-onset xanthogranuloma (AOX), adult-onset asthma and periocular xanthogranuloma (AAPOX), necrobiotic xanthogranuloma (NBX), and Erdheim-Chester disease (ECD). Therapy options vary and little is known about the long-term effect of the treatment. In this study, we will describe the clinical behaviour, effect of treatment, and long-term outcome in a consecutive series of patients with AOXGD. METHODS: This is a descriptive, retrospective study with a long follow-up term of 21 patients with histologically proven AOXGD, treated between 1989 and 2021 in the Rotterdam Eye Hospital and Erasmus MC University Medical Center. RESULTS: Twenty-one patients with histologically proven AOXGD were included. The follow-up ranged from 2-260 months (median of 67 months). Six of the nine patients with AOX were treated with surgery alone, with recurrence in two. Three received systemic therapy, with recurrence in one. All four patients with AAPOX received systemic treatment, the disease recurred in two. Two patients with NBX were treated with surgery alone, with recurrence in one. Four required additional therapy with recurrence in two. Both patients with ECD required systemic therapy. CONCLUSIONS: Recognition of AOXGD is important, in particular, because of the potential severe systemic locations in the different subtypes. Surgical excision might be a sufficient therapy for patients with AOX. Patients with AAPOX, NBX, and ECD warrant systemic therapy. Currently, there is no conclusive evidence for a superior treatment strategy, but further studies are necessary to investigate treatment options.

Accelerated growth of orbital schwannomas during pregnancy does not correlate with sex hormone- or growth factor receptor status.

Purpose: Until now, three cases of growth of an orbital schwannoma during pregnancy have been published. We aim to provide additional insight in the effect of pregnancy on orbital schwannomas. Methods: We present two additional cases of accelerated growth of orbital schwannomas during pregnancy and investigate receptor expression profiles for estrogen, progesterone, androgen, VEGF, EGF, FGF, PDGF-Rß and ki-67 in the two pregnant cases and six non-pregnant cases. Results: Case 1: A 26-year-old woman developed unilateral exophthalmos during pregnancy, with normal visual acuity and ocular motility. During a subsequent pregnancy, again the exophthalmos progressed. MRI showed a mass suggestive of schwannoma. After delivery, resection of the lesion was performed through an anterior approach. Pathology confirmed schwannoma. The expression profile was positive for estrogen- and FGF receptors and ki-67, but negative for progesterone-, androgen- and other growth factor receptors. Case 2: A 24-year-old woman presented with diplopia and unilateral pain during pregnancy. She had normal visual acuity, but a mild exophthalmos and elevation deficit. MRI revealed an extraconal mass suggestive of schwannoma. After delivery, resection was performed through an anterior approach. Pathology confirmed the diagnosis. The expression profile was positive for ki-67, but negative for sex hormone- and growth factor receptors. In the six non-pregnant cases the expression profiles varied, with only one subject showing a strong expression of estrogen-, progesterone- and androgen receptors. Conclusions: Orbital schwannomas can experience growth during pregnancy. The underlying mechanism remains unclear as hormone- and growth factor expression profiles show no correlation to the pregnant state.

Cellular angiofibroma of the orbit.

Cellular angiofibroma is a benign mesenchymal tumor most commonly located in the distal genital tract of both men and women. Although extragenital locations have been reported rarely, this is the first report of cellular angiofibroma of the orbit. A 58-year-old man presented with a mass in the left superomedial orbit since 2 years. Magnetic resonance imaging showed a well-demarcated lesion with a homogeneous intermediate signal intensity on both T1- and T2-weighted images, homogeneous contrast enhancement and high signal intensity on diffusion-weighted images. Complete excision was performed through a medial upper eyelid crease incision. Histopathology showed a vascular CD34-positive and STAT6-negative spindle cell tumor with monoallelic loss of FOXO1, indicating cellular angiofibroma.

Prognostic value of TERT promoter mutations in conjunctival melanomas in addition to clinicopathological features.

AIMS: To evaluate the prognostic value of clinical, histopathological and molecular features and to relate different treatment modalities to clinical outcome in conjunctival melanomas (CM). METHODS: Retrospective review of clinical, histopathological and BRAF V600E and telomerase reverse transcriptase (TERT) promoter mutation status and treatment modalities, correlated to recurrence and metastasis in 79 patients with CM, diagnosed between 1987 and 2015 in three tertiary referral centres in the Netherlands and Belgium. RESULTS: Out of 78 evaluable patients, recurrences occurred in 16 patients and metastasis in 12 patients (median follow-up time 35 months (0-260 months)). Tumour thickness >2 mm, pT status, the presence of epithelioid cells, ulceration and mitoses was significantly correlated with metastasis (p value 0.046, 0.01, 0.02, 0.001 and 0.003, respectively). Furthermore, CM frequently harbour BRAF V600E and TERT promoter mutations (29% and 43%, respectively). TERT promoter mutations were correlated to shorter metastasis-free survival (p value 0.002). No significant correlation was found for clinical parameters and metastatic disease. Palpebral, forniceal and caruncular melanomas were more prone to develop recurrences (p value: 0.03). Most CM were treated with excision with adjuvant therapy. CONCLUSION: In line with the recommendations in the Eighth Edition of the American Joint Committee on Cancer Staging for CM, the pathology report should include information about pT status, tumour thickness, presence of epithelioid cells, ulceration and mitoses. Furthermore, information about the presence of a TERT promoter mutation and BRAF V600E mutation is of interest for therapeutic decision making. The presence of a TERT promoter mutation is correlated to metastatic disease.

Current insights in the pathogenesis of scleritis.

Scleritis is a sight-threatening inflammation characterized by severe pain and redness of the eye. It can cause blindness by severe complications like scleral and corneal necrosis, keratitis, and uveitis. The pathogenesis of scleritis is largely unknown due to a combination of the rarity of the disease, the little available human tissue-based research material, and the lack of animal models. The immune system is assumed to play a crucial role in the pathogenesis of scleritis. Multiple clues indicate probable antigenic stimuli in scleritis, and the involvement of matrix metalloproteinases in the destruction of scleral tissue. In this article we review the current insights into the pathogenesis of scleritis, and we suggest new hypotheses by implementing knowledge of systemic autoimmune disease pathogenesis. Understanding the pathogenesis of scleritis is crucial to improve the clinical management, as well as to find novel treatment modalities.

Developmental patterns in human blood-brain barrier and blood-cerebrospinal fluid barrier ABC drug transporter expression.

When drugs exert their effects in the brain, linear extrapolation of doses from adults could be harmful for children as the blood-brain barrier (BBB) and blood-CSF barrier (BCSFB) function is still immature. More specifically, age-related variation in membrane transporters may impact brain disposition. As human data on brain transporter expression is scarce, age dependent [gestational age (GA), postnatal age (PNA), and postmenstrual age (PMA)] variation in immunohistochemical localization and staining intensity of the ABC transporters P-glycoprotein (Pgp), breast cancer resistance protein (BCRP), and multidrug resistance-associated proteins 1, 2, 4, and 5 (MRP1/2/4/5) was investigated. Post mortem brain cortical and ventricular tissue was derived from 23 fetuses (GA range 12.9-39 weeks), 17 neonates (GA range 24.6-41.3 weeks, PNA range 0.004-3.5 weeks), 8 children (PNA range 0.1-3 years), and 4 adults who died from a wide variety of underlying conditions. In brain cortical BBB, immunostaining increased with age for Pgp and BCRP, while in contrast, MRP1 and MRP2 staining intensity appeared higher in fetuses, neonates, and children, as compared to adults. BCSFB was positively stained for Pgp, MRP1, and MRP2 and appeared stable across age, while BCRP was not detected. MRP4 and MRP5 were not detected in BBB or BCSFB. In conclusion, human BBB and BCSFB ABC membrane transporters show brain location and transporter-specific maturation.

Management of cerebral azole-resistant Aspergillus fumigatus infection: A role for intraventricular liposomal-amphotericin B.

OBJECTIVES: In the pre-azole era, central nervous system (CNS) infections with Aspergillus had a dismal outcome. Survival improved with voriconazole but CNS infections caused by azole-resistant Aspergillus fumigatus preclude its use. Intravenous liposomal-amphotericin B (L-AmB) is the preferred treatment option for azole-resistant CNS infections but has suboptimal brain concentrations. METHODS: We describe three patients with biopsy-proven CNS aspergillosis where intraventricular L-AmB was added to systemic therapy. Two patients with azole-resistant aspergillosis and one patient with azole-susceptible CNS aspergillosis were treated with intraventricular L-AmB at a dose of 1mg weekly. RESULTS: We describe three patients successfully treated with a combination of intravenous and intraventricular L-AmB. All three patients survived but one patient developed serious headaches, most likely not related to this treatment. CONCLUSIONS: Intraventricular L-AmB may have a role in the treatment of therapy-refractory CNS aspergillosis when added to systemic therapy.

Intracranial actinomycosis of odontogenic origin masquerading as auto-immune orbital myositis: a fatal case and review of the literature.

BACKGROUND: Actinomycetes can rarely cause intracranial infection and may cause a variety of complications. We describe a fatal case of intracranial and intra-orbital actinomycosis of odontogenic origin with a unique presentation and route of dissemination. Also, we provide a review of the current literature. CASE PRESENTATION: A 58-year-old man presented with diplopia and progressive pain behind his left eye. Six weeks earlier he had undergone a dental extraction, followed by clindamycin treatment for a presumed maxillary infection. The diplopia responded to steroids but recurred after cessation. The diplopia was thought to result from myositis of the left medial rectus muscle, possibly related to a defect in the lamina papyracea. During exploration there was no abnormal tissue for biopsy. The medial wall was reconstructed and the myositis responded again to steroids. Within weeks a myositis on the right side occurred, with CT evidence of muscle swelling. Several months later he presented with right hemiparesis and dysarthria. Despite treatment the patient deteriorated, developed extensive intracranial hemorrhage, and died. Autopsy showed bacterial aggregates suggestive of actinomycotic meningoencephalitis with septic thromboembolism. Retrospectively, imaging studies showed abnormalities in the left infratemporal fossa and skull base and bilateral cavernous sinus. CONCLUSIONS: In conclusion, intracranial actinomycosis is difficult to diagnose, with potentially fatal outcome. An accurate diagnosis can often only be established by means of histology and biopsy should be performed whenever feasible. This is the first report of actinomycotic orbital involvement of odontogenic origin, presenting initially as bilateral orbital myositis rather than as orbital abscess. Infection from the upper left jaw extended to the left infratemporal fossa, skull base and meninges and subsequently to the cavernous sinus and the orbits.

The tarsal plate manifestation of IgG4-related disease.

PURPOSE: To describe a clinical case of bilateral biopsy-proven IgG4-related disease confined to the tarsal plate. METHOD: Interventional case report. RESULTS: A 58-year-old woman presented with a tarsal swelling in the lateral part of the upper eyelids, with focal ulceration and mucus. Histology revealed fibrotic inflammation with increased IgG4-positive plasma cells fulfilling the criteria of IgG4-related disease (IgG4-RD). Serum IgG4 levels were increased, and pathological fluorodeoxyglucose uptake at positron emission tomography/CT scanning was restricted to the upper eyelids. After treatment with oral and topical prednisone, the tarsal lesions markedly regressed. CONCLUSIONS: Periorbital IgG4-RD may be confined to the tarsal plate. Treatment with systemic and topical steroids may induce significant regression.

The treatment outcomes in IgG4-related disease.

INTRODUCTION: IgG4-related disease (IgG4-RD) is an emerging systemic inflammatory disease involving nearly all organs eventually leading to fibrosis. Prompt and adequate treatment to prevent irreversible organ damage is therefore pivotal. To evaluate the treatment outcomes, we studied a well-defined cohort of patients with IgG4-RD. METHOD: 32 patients with histologically confirmed IgG4-RD diagnosed between 1999 and April 2017 were included and reviewed for demographic and clinical characteristics. The response to treatment with glucocorticoids, disease modifying antirheumatic drugs, rituximab and other therapeutic interventions were evaluated. RESULTS: Glucocorticoids as well as rituximab appeared successful therapeutic drugs leading to clinical remission (complete or partial remission) in all patients. Recurrences, however, were frequently seen (62% versus 100%, respectively). Diseases modifying antirheumatic drugs (DMARDs), including azathioprine, methotrexate and mycophenolate mofetil were effective in less than half of the cases. A minority of patients was treated with alternative treatments including hydroxychloroquine, thalidomide and infliximab which all appeared effective. Surgical intervention and radiotherapy in local disease seemed to induce clinical remission and were associated with low recurrence rates. CONCLUSION: Glucocorticoids and rituximab induce substantial responses as well as primary surgical intervention and radiotherapy, while the efficacy of DMARDs is limited. Based on the few data available, hydroxychloroquine, infliximab and thalidomide may be promising treatment options for second or third line strategies.

Eyelid Merkel cell carcinoma in a patient treated with golimumab.

PURPOSE: To describe a clinical case of biopsy-proven Merkel cell carcinoma of the eyelid following golimumab therapy for rheumatoid arthritis (RA). METHODS: Interventional case report. RESULTS: A 73-year-old woman with a history of chronic RA presented with a right upper eyelid mass. She had been treated with golimumab (tumor necrosis factor (TNF) inhibitors) injection therapy for the past 6 months. A biopsy showed findings suggestive of a Merkel cell carcinoma of the eyelid. CONCLUSIONS: Merkel cell carcinoma may be associated with anti-TNF treatment and should be included in the differential diagnosis of an eyelid tumor in patients treated with TNF inhibitors.

GNAQ and GNA11 mutations and downstream YAP activation in choroidal nevi.

BACKGROUND: Mutations in GNAQ/11 genes are considered an early event in the development of uveal melanoma that may derive from a pre-existing nevus. The Hippo pathway, by way of YAP activation, rather than MAP kinase, has a role in the oncogenic capacity of GNAQ/11 mutations. METHODS: We investigated 16 nevi from 13 human eyes for driver GNAQ/11 mutations using droplet digital PCR and determined whether nevi are clonal by quantifying mutant nevus cell fractions. Immunohistochemistry was performed on 15 nevi to analyse YAP activation. RESULTS: For 15 out of 16 nevi, a GNAQ/11 mutation was detected in the nevus cells albeit at a low frequency with a median of 13%. Nuclear YAP, a transcriptional co-activator in the Hippo tumour-suppressor pathway, was detected in 14/15 nevi. CONCLUSIONS: Our analysis suggests that a mutation in GNAQ/11 occurs in a subset of choroidal nevus cells. We hypothesise that GNAQ/11 mutant-driven extracellular mitogenic signalling involving YAP activation leads to accumulation of wild-type nevus cells.

Infliximab for IgG4-Related Orbital Disease.

IgG4-related disease (IgG4-RD) is a systemic fibroinflammatory condition with unclear pathophysiology. It may occur as a single organ disorder, but multiorgan presentation is common and can mimic several conditions. The preferred therapy consists of steroids, but definite maintenance strategy remains unclear. The authors describe a case of a 61-year-old woman, initially diagnosed with idiopathic orbital inflammation refractory to multiple immunosuppressive agents. The disease was complicated with epilepsy, vision loss, and trismus. Treatment with various immunosuppressive agents was unsuccessful. Eventually the patient was effectively treated with infliximab. This is the second case of IgG4-RD treated with a TNF-blocker documented in literature and the first description to demonstrate its superiority over steroid sparing agents. Although speculative, TNF-blockers might exert their effect in IgG4-RD by interfering with the possible overexpressed TNF alpha due to fibrosis in this disease. Treatment with infliximab appears a good alternative for refractory IgG4-RD. However, further studies are required to define the value of infliximab in IgG4-RD.

An inflammatory condition with different faces: immunoglobulin G4-related disease.

BACKGROUND: Immunoglobulin G4-related disease (IgG4-RD) is a systemic fibro-inflammatory condition with involvement of different organs. The pathophysiological mechanism is unclear, but fibrosis is the hallmark of this disease. Early recognition is critical to avoid irreversible organ damage. Recently improved histological testing boosts the diagnostic yield. We present three cases of patients with IgG4-RD to emphasise the broad clinical presentation of this disease. CASE DESCRIPTIONS: Patient A, a 63-year-old male with bilateral orbital swelling due to IgG4-RD, was shown to suffer from IgG4-RD in a multifocal pattern as demonstrated by PET scanning. Patient B, a 53-year-old male with a long-standing abdominal mass of unknown origin, eventually proved to have IgG4-RD. Patient C was a 32-year-old male admitted with pleural effusion and pericardial tamponade. Histological diagnosis after pericardiectomy confirmed IgG4-RD. DISCUSSION: IgG4-RD has many faces and may mimic other conditions, such as malignancy and infectious diseases. Knowledge of this disease is needed to avoid unnecessary diagnostics and delay in treatment. IgG4- RD may be suspected based on specific clinical findings such as elevated serum IgG4 levels, but the diagnosis can only be established histologically. Although corticosteroids are an effective first choice of therapy, the relapse rate after this treatment remains high. The role of disease-modifying antirheumatic drugs in the treatment of IgG4-RD has not been outlined yet, but there is increasing evidence that rituximab might be an effective second-line therapy. CONCLUSION: IgG4-RD is a disease with many faces requiring early recognition and therapy to avoid permanent damage of the organs.

Escherichia coli-nitroreductase suicide gene control of human telomerase reverse transcriptase-transduced minor histocompatibility antigen-specific cytotoxic T cells.

Adoptive immunotherapy with ex vivo generated cytotoxic T lymphocytes (CTLs) is applied for the treatment of leukemia relapses or viral infections after allogeneic stem cell transplantation. A common problem of adoptive immunotherapy strategies is the ex vivo expansion of the generated T cells to sufficient numbers. CTLs can be efficiently expanded by ectopic expression of the human telomerase gene (hTert). However, hTert transduction may also increase the chance for malignant transformation. Therefore, we explored the feasibility of suicide gene control of ex vivo generated CTLs expanded through the ectopic expression of hTert. To this end, we compared the efficacy of the new Escherichia coli-nitroreductase (E. coli-Ntr) suicide gene with the well-known herpes simplex virus-thymidine kinase (HSV-Tk). Introduction of hTert provided the transduced CTLs with a distinct growth advantage over the nontransduced CTLs. The hTert-E. coli-Ntr double-transduced CTLs retained their antigen-specific functions. Treatment of hTert-E. coli-Ntr double-transduced CTLs with metronidazole significantly inhibited the proliferation to a similar extent to the treatment of hTert-HSV-Tk double-transduced CTLs with ganciclovir. This is the first application of the E. coli-nitroreductase gene for the elimination of human T cells with metronidazole.

Polyriboinosinic polyribocytidylic acid (poly(I:C)) induces stable maturation of functionally active human dendritic cells.

For vaccination strategies and adoptive immunotherapy purposes, immature dendritic cells (DC) can be generated from adherent monocytes using GM-CSF and IL-4. Presently, the only clinically applicable method to induce stable maturation of DC is the use of supernatants of activated monocytes (monocyte-conditioned medium (MCM)). MCM contains an undefined mixture of cytokines and is difficult to standardize. Here we report that stable maturation of DC can be simply induced by the addition of polyriboinosinic polyribocytidylic acid (poly(I:C)), a synthetic dsRNA clinically applied as an immunomodulator. Poly(I:C)-treated DC show a mature phenotype with high expression levels of HLA-DR, CD86, and the DC maturation marker CD83. This mature phenotype is retained for 48 h after cytokine withdrawal. In contrast to untreated DC, poly(I:C)-treated DC down-regulate pinocytosis, produce high levels of IL-12 and low levels of IL-10, induce strong T cell proliferation in a primary allo MLR, and effectively present peptide Ags to HLA class I-restricted CTL. In conclusion, we present a simple methodology for the preparation of clinically applicable mature DC.