Surgical Microanatomy of Lower Eyelid Tarsal Ectropion Repair With a Putterman Ptosis Clamp.

PURPOSE: To examine the changes in microscopic anatomy of the lower eyelid tarsal ectropion repair with the Putterman ptosis clamp and better understand the anatomical changes associated with the eyelid malposition correction. METHODS: Ten orbits from 5 fresh frozen cadaver heads, ranging in age from 53 to 77 years, were used for the dissection. For each head, a Putterman clamp tarsal ectropion repair was performed on one side, while the contralateral unoperated orbit served as a control. After performing the procedure, both orbits were exenterated and they, along with the resected specimens, were studied microscopically using Verhoeff-Masson trichrome and hematoxylin-eosin stains. RESULTS: Conjunctiva, capsulopalpebral fascia, and smooth muscle were present on all tissue specimens incarcerated within the ptosis clamp. Tarsus was present in one specimen. There was a shortening of the posterior lamella of the eyelid with advancement of the capsulopalpebral fascia on all operated specimens when compared with controls. CONCLUSION: The Putterman clamp ectropion repair works by shortening the posterior lamella of the eyelid and advancing the lower eyelid retractors superiorly. This advancement tightens the lower eyelid retractors and thus stabilizes the eyelid in a more vertical position. In addition to a lateral tendon tuck as described in the original article to tighten horizontal eyelid laxity, this procedure addresses both vertical and horizontal laxity of tarsal ectropion.

Cerebral Venous Thrombosis with Papilloedema Secondary to Skull Base Plasmacytoma.

A 60-year-old woman with history of multiple myeloma was in remission after stem cell transplant 6 years prior. She was undergoing work-up for headaches that were thought to be secondary to a right mastoiditis seen on magnetic resonance imaging (MRI). On routine eye exam, papilloedema was noted. A lumbar puncture was performed, with elevated opening pressure with normal constituents. She was an atypical age for idiopathic intracranial hypertension, and her mastoiditis raised concern for secondary cerebral venous sinus thrombosis. Magnetic resonance venography (MRV) was performed showing poor flow in the right sigmoid sinus, and computed tomography venography (CTV) showed lack of contrast enhancement distal to the right sigmoid sinus, consistent with occlusion. There was also an enhancing mass inferior to the right occipital bone. Biopsy confirmed recurrent plasma cell myeloma. She was treated with chemotherapy, radiation, and warfarin for presumed cerebral venous sinus thrombosis.

Orbito-Masticatory Syndrome.

We describe 2 unique cases of visual symptoms occurring during mastication in patients with lateral orbital wall defects. A 57-year-old man reported intermittent double vision and oscillopsia after a right fronto-temporal-orbito-zygomatic craniotomy with osteotomy of the lesser wing of the sphenoid for a complex invasive pituitary adenoma. Proptosis of the right globe was present only during mastication. Computed tomography (CT) revealed a bony defect in the right lateral orbital wall. A 48-year-old man presented with transient diplopia and scotoma in the right eye elicited by chewing. CT and magnetic resonance imaging demonstrated a bilobed lesion connecting the temporal fossa to the orbit through a defect in the right lateral orbital wall. The regional neuroanatomy and pathophysiology as pertaining to these cases are discussed.

ALS-linked mutations enlarge TDP-43-enriched neuronal RNA granules in the dendritic arbor.

Trans-activating response region (TAR) DNA-binding protein of 43 kDa (TDP-43) is an RNA-binding protein that is mutated in familial amyotrophic lateral sclerosis (ALS). Disease-linked mutations in TDP-43 increase the tendency of TDP-43 to aggregate, leading to a corresponding increase in formation of stress granules, cytoplasmic protein/RNA complexes that form in response to stress. Although the field has focused on stress granules, TDP-43 also forms other types of RNA granules. For example, TDP-43 is associated with RNA granules that are prevalent throughout the dendritic arbor in neurons. Because aggregation of TDP-43 is also important for the formation of these neuronal RNA granules, we hypothesized that disease-linked mutations might alter granule formation even in the absence of stress. We now report that ALS-linked mutations in TDP-43 (A315T and Q343R) increase the size of neuronal TDP-43 granules in the dendritic arbor of rat hippocampal neurons. The mutations correspondingly reduce the granule density, movement, and mobility of TDP-43 granules. Depolarization of rat hippocampal neurons with KCl stimulates TDP-43 granule migration into dendrites, but A315T and Q343R TDP-43 granules migrate shorter distances and into fewer dendrites than wild-type TDP-43. These findings highlight novel elements of TDP-43 biology that are affected by disease-linked mutations and suggest a neuronally selective mechanism through which TDP-43 mutations might elicit neuronal dysfunction.

Staphylococcus aureus infection of the optic nerve.

A 71-year-old woman presented with painful vision loss in the right eye followed by ophthalmoplegia. Magnetic resonance imaging demonstrated optic nerve sheath enlargement and enhancement. Biopsy of the optic nerve sheath revealed purulent and necrotic material that was positive for methicillin-sensitive Staphylococcus aureus. The patient underwent enucleation of the right eye and was treated with systemic antibiotics with clinical stabilization. Imaging, pathological and treatment aspects of optic nerve sheath abscess are discussed.

Fungal Orbital Cellulitis: Presenting Features, Management and Outcomes at a Referral Center.

PURPOSE: To report a series of patients with fungal orbital cellulitis who underwent exenteration surgery and describe presenting features, management and outcomes at a referral center. METHODS: Retrospective case series. RESULTS: From November 2011 to March 2014, four patients underwent orbital exenteration for fungal orbital cellulitis at the University of Illinois. Three patients had mucormycosis and one had aspergillosis. All patients were treated with intravenous antifungals and underwent orbital exenteration. Two patients were successfully treated with supplemental intra-orbital catheter delivery of amphotericin B. Presenting visual acuity in the affected eye ranged from 20/25 to no light perception. Some level of ophthalmoplegia was present in three patients. Significantly elevated intraocular pressure was found in two patients. All patients with mucormycosis were found to have uncontrolled diabetes mellitus. One patient had a history of myelodysplastic syndrome, chronic hepatitis C infection, polysubstance abuse and Crohn's disease. Another patient had a history of alcoholic liver cirrhosis, Crohn's disease treated with systemic immunosuppression and renal cell carcinoma. The patient with aspergillosis had myelodysplastic syndrome and portal hypertension, and the initial presentation resembled giant cell arteritis. Two of four patients died during their hospitalization. CONCLUSIONS: Fungal orbital cellulitis has a high mortality rate despite aggressive antifungal treatment and orbital exenteration performed soon after the diagnosis is confirmed. Patients often have a history of immunosuppression and the onset may be insidious. There must be a high rate of suspicion for fungal orbital cellulitis given the appropriate signs and medical history in order to avoid treatment delay.

Recurrent colon cancer in a patient with Muir-Torre syndrome: a case report.

Muir-Torre syndrome (MTS) is a rare subtype of hereditary nonpolyposis colorectal cancer syndrome caused by a defect in DNA mismatch repair leading to microsatellite instability. It is characterized by the presence of at least one sebaceous gland tumor and one internal malignancy, most commonly colorectal and endometrial tumors. These patients have a high propensity for tumorigenesis, and while strict screening protocols are in place, there are only two cases that describe the management approach to recurrent colon cancer. Here, we present a case of recurrent colorectal cancer in a patient with MTS, and describe how it was managed at our facility by a multidisciplinary team.

A cost-effectiveness analysis of avelumab plus best supportive care versus best supportive care alone as first-line maintenance treatment for patients with locally advanced or metastatic urothelial carcinoma in Taiwan.

BACKGROUND: Patients with locally advanced or metastatic urothelial carcinoma have limited treatment options and a poor prognosis. The JAVELIN Bladder 100 trial showed that avelumab as first-line maintenance plus best supportive care significantly prolonged overall survival and progression-free survival versus best supportive care alone in patients with locally advanced or metastatic urothelial carcinoma that had not progressed with first-line platinum-containing chemotherapy. AIMS: We assessed whether avelumab plus best supportive care is a cost-effective treatment option versus best supportive care alone in this patient group in Taiwan. METHODS AND RESULTS: A partitioned survival model was used to estimate the costs and effects of avelumab plus best supportive care versus best supportive care alone over a 20-year time horizon from the perspective of Taiwan's National Health Insurance Administration. Patient-level data from JAVELIN Bladder 100 on efficacy, safety, utility, and time on treatment were analyzed to provide parameters for the model. Log-normal and Weibull distributions were used for overall survival and progression-free survival, respectively. Costs of healthcare resources, drug acquisition, adverse events, and progression were identified through publicly available data sources and clinician interviews. The model estimated total costs, life years, and quality-adjusted life years. In the modeled base case, avelumab plus best supportive care increased survival versus best supportive care alone by 0.79 life years (2.93 vs. 2.14) and 0.61 quality-adjusted life years (2.15 vs. 1.54). The incremental cost-effectiveness ratio for avelumab plus best supportive care versus best supportive care alone was NT$1 827 680. Most (78%) of the probabilistic sensitivity analyses fell below three times the gross domestic product per capita. Scenario analysis indicated that life year and quality-adjusted life year gains were most sensitive to alternative survival extrapolations for both avelumab plus best supportive care and best supportive care alone. CONCLUSION: Avelumab first-line maintenance therapy combined with best supportive care was determined as a cost-effective treatment strategy for patients in Taiwan diagnosed with locally advanced or metastatic urothelial carcinoma that had not progressed with platinum-containing chemotherapy.

A cost-utility analysis of avelumab for metastatic Merkel cell carcinoma in Taiwan.

BACKGROUND: Metastatic Merkel cell carcinoma (mMCC) has traditionally been managed with palliative chemotherapy regimens or best supportive care (BSC). Avelumab, a novel anti-programmed death-ligand 1 (PD-L1) human monoclonal antibody for mMCC treatment, is being studied in the pivotal JAVELIN Merkel 200 trial. AIM: Incorporating trial results, this analysis aimed to evaluate the cost-utility of avelumab in Taiwan. METHODS AND RESULTS: A de novo partitioned-survival model with three key health states related to survival (progression-free disease, progressed disease, and death) was applied in this study. The data of clinical efficacy, safety, and patient utilities were obtained from the JAVELIN Merkel 200 trial, literature review, and Taiwanese clinical expert opinion. Cost-utility analysis was performed, and results were presented as cost per quality-adjusted life year (QALY) gained. For treatment-naïve patients, the incremental cost-effectiveness ratios (ICERs) for avelumab vs BSC and avelumab vs chemotherapy were US$44885.06 and US$42993.06 per QALY gained, respectively. As to treatment-experienced mMCC patients, avelumab was associated with ICERs of US$27243.06 (vs BSC)/US$26557.43 (vs chemotherapy) per QALY gained. All ICERs remained consistently within the willingness-to-pay (WTP) threshold of US$53,333.33 per QALY gained. CONCLUSION: This study demonstrated avelumab to be a cost-effective treatment option for both treatment-experienced and treatment-naïve mMCC patients with very poor prognosis in Taiwan.

Social Media Engagement at Academic Conferences: Report of the Association of Pathology Chairs 2018 and 2019 Annual Meeting Social Media Committee.

The use of social media at academic conferences is expanding, and platforms such as Twitter are used to share meeting content with the world. Pathology conferences are no exception, and recently, pathology organizations have promoted social media as a way to enhance meeting exposure. A social media committee was formed ad hoc to implement strategies to enhance social media involvement and coverage at the 2018 and 2019 annual meetings of the Association of Pathology Chairs. This organized approach resulted in an 11-fold increase in social media engagement compared to the year prior to committee formation (2017). In this article, the social media committee reviews the strategies that were employed and the resultant outcome data. In addition, we categorize tweets by topic to identify the topics of greatest interest to meeting participants, and we discuss the differences between Twitter and other social media platforms. Lastly, we review the existing literature on this topic from 23 medical specialties and health care fields.

Alveolar rhabdomyosarcoma with neuroendocrine/neuronal differentiation: report of 3 cases.

The aim of this study is to report the clinicopathologic characteristics of 3 cases of alveolar rhabdomyosarcoma with neuroendocrine/neuronal differentiation. Specimens of 3 cases of alveolar rhabdomyosarcoma were studied using histologic, immunohistochemical, ultrastructural, and molecular genetic techniques. The patients were a 19-year-old man with metastatic alveolar rhabdomyosarcoma in a groin lymph node, a 16-year-old girl with alveolar rhabdomyosarcoma of the perineum, and a 20-year-old man with recurrent orbital alveolar rhabdomyosarcoma. Microscopically, case 1 was composed of compact sheets of medium to large tumor cells. Cases 2 and 3 were small blue round cell tumors. Cases 1 and 3 were solid throughout, whereas case 2 demonstrated alveolar and solid architecture. By immunohistochemistry, the following markers were positive: desmin (3/3), myogenin (3/3), synaptophysin (3/3), and chromogranin (2/3). Ultrastructurally, sarcomeric filaments were seen in all cases, while neuroendocrine granules were detected only in case 1. PAX:FKHR fusion transcript was identified in case 2, case 3 had a variant PAX3 transcript, and case 1 was negative. The data presented expands the known differentiation of alveolar rhabdomyosarcoma.

Self-Directed and Lifelong Learning: the 5th "S" for TBL™ Application Exercises?

This paper describes a pilot of an innovation to TBL™ as a means to add a fifth "S", self-directed learning (SDL) and life-long learning (LLL), to the 4S application exercise framework. It is important for TBL™ to explicitly address SDL and LLL to enhance student learning and meet accreditation standards.

A rare autism-associated MINT2/APBA2 mutation disrupts neurexin trafficking and synaptic function.

MINT2/APBA2 is a synaptic adaptor protein involved in excitatory synaptic transmission. Several nonsynonymous coding variants in MINT2 have been identified in autism spectrum disorders (ASDs); however, these rare variants have not been examined functionally and the pathogenic mechanisms are unknown. Here, we examined the synaptic effects of rat Mint2 N723S mutation (equivalent to autism-linked human MINT2 N722S mutation) which targets a conserved asparagine residue in the second PDZ domain of Mint2 that binds to neurexin-1α (Nrxn1α), a presynaptic cell-adhesion protein implicated in ASDs. We show the N723S mutation impairs Nrxn1α stabilization and trafficking to the membrane while binding to Nrxn1α remains unaffected. Using time-lapse imaging in primary mouse neurons, we found that the N723S mutant had more immobile puncta at neuronal processes compared to Mint2 wild type. We therefore, reasoned that the N723S mutant may alter the co-transport of Nrxn1α at axonal processes to presynaptic terminals. Indeed, we found the N723S mutation affected Nrxn1α localization at presynaptic terminals which correlated with a decrease in Nrxn-mediated synaptogenesis and miniature event frequency in excitatory synapses. Together, our data reveal Mint2 N723S leads to neuronal dysfunction, in part due to alterations in Nrxn1α surface trafficking and synaptic function of Mint2.

Cellular function of neuropathy target esterase in lysophosphatidylcholine action.

Neuropathy target esterase (NTE) plays critical roles in embryonic development and maintenance of peripheral axons. It is a secondary target of some organophosphorus toxicants including analogs of insecticides and chemical warfare agents. Although the mechanistic role of NTE in vivo is poorly defined, it is known to hydrolyze lysophosphatidylcholine (LPC) in vitro and may protect cell membranes from cytotoxic accumulation of LPC. To determine the cellular function of NTE, Neuro-2a and COS-7 cells were transfected with a full-length human NTE-containing plasmid yielding recombinant NTE (rNTE). We find the same inhibitor sensitivity and specificity profiles for rNTE assayed with LPC or phenyl valerate (a standard NTE substrate) and that this correlation extends to the LPC hydrolases of human brain, lymphocytes and erythrocytes. All of these LPC hydrolases are therefore very similar to each other in respect to a conserved inhibitor binding site conformation. NTE is expressed in brain and lymphocytes and contributes to LPC hydrolase activities in these tissues. The enzyme or enzymes responsible for erythrocyte LPC hydrolase activity remain to be identified. We also show that rNTE protects Neuro-2a and COS-7 cells from exogenous LPC cytotoxicity. Expression of rNTE in Neuro-2a cells alters their phospholipid balance (analyzed by liquid chromatography-mass spectrometry with single ion monitoring) by lowering LPC-16:0 and LPC-18:0 and elevating glycerophosphocholine without a change in phosphatidylcholine-16:0/18:1 or 16:0/18:2. NTE therefore serves an important function in LPC homeostasis and action.

Cyst Masquerading as Inadvertent Bleb After a Scleral-Fixated Intraocular Lens in Marfan Syndrome: A Case Report.

INTRODUCTION: To present a case of an epithelial inclusion cyst masquerading as an inadvertent bleb in a patient with Marfan syndrome. CASE REPORT: A woman with Marfan syndrome presented with a subluxed crystalline lens in her right eye, which progressively subluxed over the following 2 years. A lensectomy was performed with placement of an anterior chamber intraocular lens (IOL); however, the patient experienced blurred vision and photopsias and preferred IOL explantation. The IOL was removed and a scleral-fixated posterior chamber IOL was placed. Vision improved with an uncomplicated postoperative course. Five months later, the patient experienced sudden onset redness and sharp pain in this eye. A 3-mm cystic lesion with tan material was found over a prior scleral incision site. Intraocular pressure was normal and no aqueous leaked from the lesion. Owing to concerns of an infected inadvertent bleb, treatment with topical and oral antibiotics was started, but the lesion did not change in appearance and the patient experienced persistent pain. The lesion was surgically excised and histopathology revealed a conjunctival epithelial inclusion cyst with intralesional keratin. A month later, another conjunctival inclusion cyst developed and was excised per patient preference. CONCLUSION: Marfan syndrome is characterized by defects in the FBN1 gene and may theoretically lead to an abnormal sclera, increasing the risk of bleb formation after scleral incision. Distinguishing between a filtering bleb and an epithelial inclusion cyst is critical in patient care. Although retained keratin from a cyst may mimic a bleb with purulence, intraocular pressure, aqueous leakage, and response to topical antibiotics may help distinguish between the two.

Modeling the behavior of uveal melanoma in the liver.

PURPOSE: To model the behavior of uveal melanoma in the liver. METHODS: A 15-muL suspension of metastatic MUM2B or either primary OCM1 or M619 uveal melanoma cells was injected into the liver parenchyma of 105 CB17 SCID mice through a 1-cm abdominal incision. Animals were killed at 2, 4, 6, or 8 weeks after injection. Before euthanatization, 3% FITC-BSA buffer was injected into the retro-orbital plexus of one eye of three mice. Liver tissues were examined by light and fluorescence microscopy, and were stained with human anti-laminin. Vasculogenic mimicry patterns were reconstructed from serial laser scanning confocal microscopic stacks. RESULTS: OCM1a cells formed microscopic nodules in the mouse liver within 2 weeks after injection and metastasized to the lung 6 weeks later. By contrast, M619 and MUM2B cells formed expansile nodules in the liver within 2 weeks and gave rise to pulmonary metastases within 4 weeks after injection. Vasculogenic mimicry patterns, composed of human laminin and identical with those in human primary and metastatic uveal melanomas, were detected in the animal model. The detection of human rather than mouse laminin in the vasculogenic mimicry patterns in this model demonstrates that these patterns were of tumor cell origin and were not co-opted from the mouse liver microenvironment. CONCLUSIONS: There are currently no effective treatments for metastatic uveal melanoma. This direct-injection model focuses on critical interactions between the tumor cell and the liver. It provides for translationally relevant approaches to the development of new modalities to detect small tumor burdens in patients, to study the biology of clinical dormancy of metastatic disease in uveal melanoma, to design and test novel treatments to prevent the emergence of clinically manifest liver metastases after dormancy, and to treat established uveal melanoma metastases.