The value of SPECT/CT imaging of lacrimal glands as a means of assessing the activity of Graves’ orbitopathy

Background: Graves’ orbitopathy (GO) is an autoimmune disease with mechanical impairment of orbital muscles and lacrimal gland dysfunction. The frequently used methods of assessing GO activity include: Clinical Activity Score (CAS), computed tomography (CT), and magnetic resonance imaging (MRI). These approaches are mainly associated with orbital muscles, however, there are not many studies that focus on the lacrimal gland inflammation of GO patients. Objective: The aim of this study is to assess the usefulness of 99mTc-DTPA SPECT/CT in evaluating the lacrimal gland inflammation in Graves orbitopathy, as compared with other methods. Methods: A retrospective analysis of 48 patients with active GO compared with 33 controls was conducted. All subjects underwent clinical-endocrinological analyses, CAS evaluation, CT scans, and SPECT/CT examination. Lacrimal gland dimensions were determined and analyzed. Results: The lacrimal glands in patients with GO were significantly larger in all measured dimensions (p < 0.001) on CT scans relative to those in controls. Increased lacrimal gland DTPA uptake ratios (p < 0.001) were displayed in active GO patients compared to controls and were also correlated with TRAb levels. The cut-off value for discriminating active and inactive disease was calculated to be 1.735, with specificity of 82.6% and sensitivity of 74.2%. SPECT/CT uptake ratios and CAS values were positively correlated in all GO patients. SPECT/CT uptake ratios were also positively correlated with CT measurements including lacrimal gland volume and coronal width in GO patients. Conclusions: These data indicated that lacrimal gland SPECT/CT images can serve as a good tool for assessing the inflammation and disease activity of GO.

Review of the Literature on Existing Management of Dry Eye Disease

Dry eye disease (DED) is a multifactorial disease in which the tear film’s homeostasis is lost, along with other ocular symptoms such as tear film instability and high osmolarity, neurosensory abnormalities, and ocular surface inflammation and damage. DED is a condition of lacrimal apparatus which is responsible for tear production. The tear film is a mixture of mucin, aqueous (water and solutes like NacI, sugar, urea, proteins,), lipids secreted by goblet cells, lacrimal glands, and meibomian glands, respectively. It keeps the eye moist, provides oxygen to the cornea, and has antibacterial properties. The lipid layer prevents the evaporation of the aqueous. DED is categorized into (i)Aqueous-tear deficiency, characterized by a deficiency of lacrimal glands to secrete tears, (ii)Evaporative DED, associated with increased tear loss by evaporation because there is a deficiency of the meibomian glands. The mechanism of DED might be loss of tear through evaporation or insufficient aqueous production or a combination of the two. DED is a widespread eye problem, which is often left untreated. It causes irritation, itching, dryness, foreign body sensation, and discomfort; severe case causes conjunctival congestion, keratinization, erosion of the corneal epithelium, and plaque formation. If left Univision- threatening vision-threatening, leading to complications like corneal ulceration and perforation. Various clinical tests are used to diose DED, including tear breakup time, tear osmolarity, Schirmer test, Rose Bengal staining, and expression of inflammatory markers. There is no cure for DED at present. The following modalities are used for its treatment: use of punctual and canalicular plugs, artificial tear products like polyethylene glycol/propylene glycol with guar HP, consuming food rich in omega-three fatty acids, antioxidants zeaxanthin, and lutein, Use of anti-inflammatory drugs, mucolytics, secretagogues. Reducing or avoiding mild risk factors like prolonged reading, prolonged use of contact lenses, excessive screen time, etc. Treatment of causative disease. Appropriate management and establishing reasonable patient expectations are necessary to ensure patient satisfaction and adherence to the treatment.

Clinical, Radiological and Histopathological Features of Patients With Lacrimal Gland Enlargement

Background: The purpose of this study was to describe the radiologic and histopathologic features of lacrimal gland in patients presenting with lacrimal gland enlargement. Methods: We retrospectively retrieved the data of patients with lacrimal gland enlargement in Farabi Eye Hospital between 2012 and 2017. These data included demographics, the patients’ facial photographs, orbital CT-scans, and histopathological findings of lacrimal gland biopsies. Results: Forty-seven patients (15 men and 32 women) were enrolled in this study with a median age of 37.9 years (range, 15–79 years). Histopathologic diagnoses were chronic dacryoadenitis in 26 cases (55.32%), IgG4-related disease in 6 patients (12.77%), two cases of acute dacryoadenitis, two cases of non-necrotizing granulomatous inflammation, two cases of Non-Hodgkin’s B-cell lymphoma, two cases of adenoid cystic carcinoma and two cases of mixed tumor (4.26% each), as well as one case of conjunctival epithelial cyst, and one case of benign lymphoid tissue and fibrofatty tissue (2.13%). In two samples (4.26%), biopsy revealed normal lacrimal glands. Interestingly, in two cases with relapsing lacrimal gland enlargement, different histopathologic diagnoses were found in biopsies taken from each lacrimal gland at different times. The average size of enlarged lacrimal glands was 19.67 mm × 7.06 mm on axial CT scan and 19.44 mm × 6.20 mm on coronal CT scan. Conclusion: Tissue biopsy is needed for diagnosis of lacrimal gland enlargement because it is difficult to distinguish the type of the lacrimal gland pathology based solely on clinical or radiological presentation.

First-In-Human Results on the Biodistribution, Pharmacokinetics, and Dosimetry of [177Lu]Lu-DOTA.SA.FAPi and [177Lu]Lu-DOTAGA.(SA.FAPi)2

Recently, great interest has been gained regarding fibroblast activation protein (FAP) as an excellent target for theranostics. Several FAP inhibitor molecules such as [68Ga]Ga-labelled FAPI-02, 04, 46, and DOTA.SA.FAPi have been introduced and are highly promising molecular targets from the imaging point of view. FAP inhibitors introduced via bifunctional DOTA and DOTAGA chelators offer the possibility to complex Lutetium-177 due to an additional coordination site, and are suitable for theranostic applications owing to the increased tumor accumulation and prolonged tumor retention time. However, for therapeutic applications, very little has been accomplished, mainly due to residence times of the compounds. In an attempt to develop a promising therapeutic radiopharmaceutical, the present study aimed to evaluate and compare the biodistribution, pharmacokinetics, and dosimetry of [177Lu]Lu-DOTA.SA.FAPi, and [177Lu]Lu-DOTAGA.(SA.FAPi)2 in patients with various cancers. The FAPi agents, [177Lu]Lu-DOTA.SA.FAPi and [177Lu]Lu-DOTAGA.(SA.FAPi)2, were administered in two different groups of patients. Three patients (mean age—50 years) were treated with a median cumulative activity of 2.96 GBq (IQR: 2.2–3 GBq) [177Lu]Lu-DOTA.SA.FAPi and seven (mean age—51 years) were treated with 1.48 GBq (IQR: 0.6–1.5) of [177Lu]Lu-DOTAGA.(SA.FAPi)2. Patients in both the groups underwent serial imaging whole-body planar and SPECT/CT scans that were acquired between 1 h and 168 h post-injection (p.i.). The residence time and absorbed dose estimate in the source organs and tumor were calculated using OLINDA/EXM 2.2 software. Time versus activity graphs were plotted to determine the effective half-life (Te) in the whole body and lesions for both the radiotracers. Physiological uptake of [177Lu]Lu-DOTA.SA.FAPi was observed in the kidneys, colon, pancreas, liver, gall bladder, oral mucosa, lacrimal glands, and urinary bladder contents. Physiological biodistribution of [177Lu]Lu-DOTAGA.(SA.FAPi)2 involved liver, gall bladder, colon, pancreas, kidneys, and urinary bladder contents, lacrimal glands, oral mucosa, and salivary glands. In the [177Lu]Lu-DOTA.SA.FAPi group, the highest absorbed doses were noted in the kidneys (0.618 ± 0.015 Gy/GBq), followed by the colon (right colon: 0.472 Gy/GBq and left colon: 0.430 Gy/GBq). In the [177Lu]Lu-DOTAGA.(SA.FAPi)2 group, the colon received the highest absorbed dose (right colon: 1.160 Gy/GBq and left colon: 2.870 Gy/GBq), and demonstrated a significantly higher mean absorbed dose than [177Lu]Lu-DOTA.SA.FAPi (p < 0.011). [177Lu]Lu-DOTAGA.(SA.FAPi)2 had significantly longer median whole-body Te compared to that of [177Lu]Lu-DOTA.SA.FAPi [46.2 h (IQR: 38.5–70.1) vs. 23.1 h (IQR: 17.8–31.5); p-0.0167]. The Te of tumor lesions was significantly higher for [177Lu]Lu-DOTAGA.(SA.FAPi)2 compared to [177Lu]Lu-DOTA.SA.FAPi [86.6 h (IQR: 34.3–94.6) vs. 14 h (IQR: 12.8–15.5); p-0.0004]. The median absorbed doses to the lesions were 0.603 (IQR: 0.230–1.810) Gy/GBq and 6.70 (IQR: 3.40–49) Gy/GBq dose per cycle in the [177Lu]Lu-DOTA.SA.FAPi, and [177Lu]Lu-DOTAGA.(SA.FAPi)2 groups, respectively. The first clinical dosimetry study demonstrated significantly higher tumor absorbed doses with [177Lu]Lu-DOTAGA.(SA.FAPi)2 compared to [177Lu]Lu-DOTA.SA.FAPi. [177Lu]Lu-DOTAGA.(SA.FAPi)2 is safe and unveiled new frontiers to treat various end-stage cancer patients with a theranostic approach.

Autoimmune Epithelitis and Chronic Inflammation in Sjögren’s Syndrome-Related Dry Eye Disease

Autoimmune epithelitis and chronic inflammation are one of the characteristic features of the immune pathogenesis of Sjögren’s syndrome (SS)-related dry eye disease. Autoimmune epithelitis can cause the dysfunction of the excretion of tear fluid and mucin from the lacrimal glands and conjunctival epithelia and meibum from the meibomian glands. The lacrimal gland and conjunctival epithelia express major histocompatibility complex class II or human leukocyte antigen-DR and costimulatory molecules, acting as nonprofessional antigen-presenting cells for T cell and B cell activation in SS. Ocular surface epithelium dysfunction can lead to dry eye disease in SS. Considering the mechanisms underlying SS-related dry eye disease, this review highlights autoimmune epithelitis of the ocular surface, chronic inflammation, and several other molecules in the tear film, cornea, conjunctiva, lacrimal glands, and meibomian glands that represent potential targets in the treatment of SS-related dry eye disease.

Can volumetric modulated arc radiation therapy reduce organ at risk dose in stage 4 sinonasal tumors in dogs treated with boost irradiation?

Intensity modulated radiation therapy (IMRT) introduced marked changes to cancer treatment in animals by reducing dose to organs at risk (OAR). As the next technological step, volumetric modulated arc therapy (VMAT) has advantages (increased degrees-of-freedom, faster delivery) compared to fixed-field IMRT. Our objective was to investigate a possible advantage of VMAT over IMRT in terms of lower OAR doses in advanced-disease sinonasal tumors in dogs treated with simultaneously-integrated boost radiotherapy. A retrospective, analytical, observational study design was applied using 10 pre-existing computed tomography datasets on dogs with stage 4 sinonasal tumors. Each dataset was planned with both, 5-field IMRT and 2 arc VMAT with 10x4.83 Gy to the gross tumor volume and 10x4.2 Gy to the planning target volume. Adequate target dose coverage and normal tissue complication probability of brain ≤5% was required. Dose constraints aspired to were D60 <15 Gy for eyes, D2 <35.4 Gy for corneae, and Dmean <20 Gy for lacrimal glands. OAR dose was statistically significantly higher in IMRT plans than in VMAT plans. Median eye D60% was 18.5 Gy (interquartile range (IQR) 17.5) versus 16.1 Gy (IQR 7.4) (p = 0.007), median lacrimal gland dose 21.8 Gy (IQR 20.5) versus 18.6 Gy (IQR 7.0) (p = 0.013), and median cornea D2% 45.5 Gy (IQR 6.8) versus 39.9 Gy (IQR 10.0) (p<0.005) for IMRT versus VMAT plans, respectively. Constraints were met in 21/40 eyes, 7/40 corneae, and 24/40 lacrimal glands. Median delivery time was significantly longer for IMRT plans than for VMAT plans (p<0.01). Based on these results, VMAT plans were found to be superior in sparing doses to eyes, lacrimal glands, corneae. However, not all ocular OAR constraints could be met while ensuring adequate dose coverage and restricting brain toxicity risk for both planning techniques.

Whole Brain Mapping of Neurons Innervating Extraorbital Lacrimal Glands in Mice and Rats of Both Genders

The extraorbital lacrimal glands (ELGs) secret tears to maintain a homeostatic environment for ocular surfaces, and pheromones to mediate social interactions. Although its distinct gender-related differences in mice and rats have been identified, its comprehensive histology together with whole-brain neuronal network remain largely unknown. The primary objective of the present study was to investigate whether sex-specific differences take place in histological and physiological perspectives. Morphological and histological data were obtained via magnetic resonance imaging (MRI), hematoxylin-eosin (HE) staining in mice and rats of both genders. The innervating network was visualized by a pseudorabies virus (PRV) mediated retrograde trans-multi-synaptic tracing system for adult C57BL6/J mice of both genders. In terms of ELGs' anatomy, mice and rats across genders both have 7 main lobes, with one exception observed in female rats which have only 5 lobes. Both female rats and mice generally have relatively smaller shape size, absolute weight, and cell size than males. Our viral tracing revealed a similar trend of innervating patterns antero-posteriorly, but significant gender differences were also observed in the hypothalamus (HY), olfactory areas (OLF), and striatum (STR). Brain regions including piriform area (Pir), post-piriform transition area (TR), central amygdalar nucleus (CEA), medial amygdalar nucleus (MEA), lateral hypothalamic area (LHA), parasubthalamic nucleus (PSTN), pontin reticular nucleus (caudal part) (PRNc), and parabrachial nucleus, (PB) were commonly labeled. In addition, chemical isotope labeling-assisted liquid chromatography-mass spectrometry (CIL-LC-MS) and nuclear magnetic resonance spectroscopy (NMR spectroscopy) were performed to reveal the fatty acids and metabolism of the ELGs, reflecting the relationship between pheromone secretion and brain network. Overall, our results revealed basic properties and the input neural networks for ELGs in both genders of mice, providing a structural basis to analyze the diverse functions of ELGs.

P27 Lymphoma-mimicker of IgG4-related dacryoadenitis and sialadenitis

Case report - Introduction Major salivary gland (sialadenitis) and lacrimal gland (dacryoadenitis) involvement can be a common feature of IgG4-related disease. There can be involvement of lacrimal and parotid gland which was previously called as Mikulicz disease and/or submandibular gland enlargement which was previously called Küttner tumour. These were previously mistakenly considered to be subcategories of Sjogren’s syndrome, but are now classified as IgG4-related disease. Here we discuss a case report of a patient who presented with bilateral dacryoadenitis and unilateral submandibular gland enlargement which initially was thought to be IgG4-related disease but turned out to be low-grade lymphoma. Case report - Case description A 15-year-old boy presented with 6-month history of bilateral eyelid swelling. The swelling was more on the lateral side of the eyelids and was painless. It had come on suddenly over a couple of days. No history of weight loss, dry eyes, dry mouth, joint issues or skin rashes or any other symptoms. Physical examination revealed bilateral ptosis, no visual impairment and systemic examination revealed an enlarged right submandibular gland. He had initially been to a local hospital where he had investigations which included autoimmune screen including ANA, ENA, ANCA, dsDNA, serum ace and complement levels which were all negative. C1 esterase inhibitor was normal. Routine bloods including complete blood count, urea and electrolytes, thyroid stimulating hormone and erythrocyte sedimentation rate were within normal limits. Urine albumin to creatinine ratio was not raised. Hepatitis serology including Hepatitis B & C and HIV was negative. Ultrasound abdomen was unremarkable. CT scan of orbits showed bilateral enlarged lacrimal glands with patchy post contrast enhancement and the glands extending up to insertion of lateral rectus muscle. CT chest some enlarged axillary lymph nodes and nodes in lung query infective etiology. CT abdomen and pelvis was unremarkable. Ultrasound neck showed right submandibular node enlargement with colour doppler showing increased vascularity. Fine needle aspirate of the submandibular gland showed reactive lymphoid hyperplasia. He was given two short courses of steroids and each time the swelling rapidly responded to the steroids but recurred on cessation of the steroids. IgG subset analyses revealed elevated IgG4 levels of 1152mg/dl. The differential here was IgG4-related disease but as there was no clear tissue diagnosis a core biopsy of the right submandibular gland was done. This revealed tissue suspicious of low grade (extranodal marginal zone and mucosa-associated lymphoid tissue [MALT]) lymphoma and excision biopsy was performed for definitive diagnosis. Case report - Discussion IgG4-related disease is an immune mediated fibroinflammatory condition which can affect a variety of organs and can present as tumour-like enlargement and/or organ dysfunction. The pathological findings in IgG4-related disease are lymphoplasmocytic infiltrates of IgG4-positive cells along with increased levels of serum IgG4 levels. Salivary and lacrimal glands can be commonly affected and present as enlargement, which is usually painless and bilateral. The combination of lacrimal gland enlargement with both parotid and submandibular gland enlargement is called IgG4-related Mikulicz disease. Apart from salivary glands, another commonly affected organ is the pancreas which can present as a pancreatic mass and painless jaundice, sclerosing cholangitis, retroperitoneal fibrosis, aortitis and periaortitis. Less commonly it can affect thyroid, kidney and lungs. Early recognition, diagnoses and treatment is important due to the fibroinflammatory nature of the disease. Malignancy is always in the differential and should be excluded. Steroids are the mainstay of treatment. If patients experience flare, rituximab can be added. Diagnosis should be confirmed with biopsy but histopathological findings are never alone diagnostic of IgG4-related disease and should be interpreted with clinical, serological and radiological findings. Case report - Key learning points Although this patient had typical presentation of IgG4-related disease with painless enlargement of salivary and lacrimal glands and elevated IgG4 serum levels, biopsy was imperative to get to the diagnoses of low-grade lymphoma and fine needle aspirate was not adequate. As mentioned above, biopsy in IgG4-related disease will confirm the diagnosis provided there are other supporting features (radiological and serological). However, it is imperative for excluding other important diseases like lymphoproliferative disorders.