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Significance: Spatial frequency domain imaging (SFDI) applies patterned near-infrared illumination to quantify the optical properties of subsurface tissue. The periocular region is unique due to its complex ocular adnexal anatomy. Although SFDI has been successfully applied to relatively flat in vivo tissues, regions that have significant height variations and curvature may result in optical property inaccuracies., Aim: We characterize the geometric impact of the periocular region on SFDI imaging reliability., Approach: SFDI was employed to measure the reduced scattering coefficient ( μ s ' ) and absorption coefficient ( μ a ) of the periocular region in a cast facial tissue-simulating phantom by capturing images along regions of interest (ROIs): inferior temporal quadrant (ITQ), inferior nasal quadrant (INQ), superior temporal quadrant (STQ), central eyelid margin (CEM), rostral lateral nasal bridge (RLNB), and forehead (FH). The phantom was placed on a chin rest and imaged nine times from an "en face" or "side profile" position, and the flat back of the phantom was measured 15 times., Results: The measured μ a and μ s ' of a cast facial phantom are accurate when comparing the ITQ, INQ, STQ, and FH to its flat posterior surface. Paired t tests of ITQ, INQ, STQ, and FH μ a and μ s ' concluded that there is not enough evidence to suggest that imaging orientation impacted the measurement accuracy. Regions of extreme topographical variation, i.e., CEM and RLNB, did exhibit differences in measured optical properties., Conclusions: We are the first to evaluate the geometric implications of wide-field imaging along the periocular region using a solid tissue-simulating facial phantom. Results suggest that the ITQ, INQ, STQ, and FH of a generalized face have minimal impact on the SFDI measurement accuracy. Areas with heightened topographic variation exhibit measurement variability. Device and facial positioning do not appear to bias measurements. These findings confirm the need to carefully select ROIs when measuring optical properties along the periocular region., (© 2024 The Authors.)

Purpose: To explore if orbital fat-to-muscle ratio (FMR) is predictive of whether surgical decompression or teprotumumab leads to greater proptosis reduction in thyroid eye disease (TED)., Methods: A single-center retrospective cohort study comparing surgical decompression with teprotumumab according to FMR. All TED patients completing an 8-dose course of teprotumumab between January 2020 and September 2022 and all patients undergoing bony orbital decompression from January 2017 to December 2019 were included. Subjects were excluded if they were <18 years, received both surgical decompression and teprotumumab, or lacked orbital imaging. The primary exposure variable was teprotumumab or surgical decompression. The secondary exposure variable was baseline FMR. The primary outcome measure was change in proptosis (mm)., Results: Thirty-eight patients, mean age 53.5 years (±11.4), were included in the teprotumumab group and 160 patients, mean age 48 years (±11.1), in the surgical group. Average proptosis reduction after teprotumumab and surgical decompression was 3 mm (±1.44) and 5 mm (±1.75), respectively. The FMR was stratified at the median of 1.80. In subjects with FMR < 1.80, teprotumumab showed equivalent proptosis reduction compared to surgical decompression, -0.33 mm (SE 1.32) p  = .802. In subjects with FMR ≥ 1.80, surgical decompression led to significantly more proptosis reduction than teprotumumab, 3.01 mm (SE 0.54), p  < .001., Conclusions: Baseline FMR can be used to counsel patients as to proptosis reduction with teprotumumab versus surgery. Subjects with low FMR obtain comparable proptosis reduction with teprotumumab or surgery, whereas high FMR is associated with more significant proptosis reduction following surgery over teprotumumab.

Purpose: To assess whether transcutaneous retrobulbar amphotericin B injections (TRAMB) reduce exenteration rate without increasing mortality in rhino-orbital-cerebral mucormycosis (ROCM)., Methods: In this retrospective case-control study, 46 patients (51 eyes) with biopsy-proven ROCM were evaluated at 9 tertiary care institutions from 1998 to 2021. Patients were stratified by radiographic evidence of local orbital versus extensive involvement at presentation. Extensive involvement was defined by MRI or CT evidence of abnormal or loss of contrast enhancement of the orbital apex with or without cavernous sinus, bilateral orbital, or intracranial extension. Cases (+TRAMB) received TRAMB as adjunctive therapy while controls (-TRAMB) did not. Patient survival, globe survival, and vision/motility loss were compared between +TRAMB and -TRAMB groups. A generalized linear mixed effects model including demographic and clinical covariates was used to evaluate the impact of TRAMB on orbital exenteration and disease-specific mortality., Results: Among eyes with local orbital involvement, exenteration was significantly lower in the +TRAMB group (1/8) versus -TRAMB (8/14) ( p  = 0.04). No significant difference in mortality was observed between the ±TRAMB groups. Among eyes with extensive involvement, there was no significant difference in exenteration or mortality rates between the ±TRAMB groups. Across all eyes, the number of TRAMB injections correlated with a statistically significant decreased rate of exenteration ( p  = 0.048); there was no correlation with mortality., Conclusions: Patients with ROCM with local orbital involvement treated with adjunctive TRAMB demonstrated a lower exenteration rate and no increased risk of mortality. For extensive involvement, adjunctive TRAMB does not improve or worsen these outcomes.

Background: Acute invasive fungal sinusitis (AIFS) is an aggressive disease that requires prompt diagnosis and multidisciplinary treatment given its rapid progression. However, there is currently no consensus on diagnosis, prognosis, and management strategies for AIFS, with multiple modalities routinely employed. The purpose of this multi-institutional and multidisciplinary evidence-based review with recommendations (EBRR) is to thoroughly review the literature on AIFS, summarize the existing evidence, and provide recommendations on the management of AIFS., Methods: The PubMed, EMBASE, and Cochrane databases were systematically reviewed from inception through January 2022. Studies evaluating management for orbital, non-sinonasal head and neck, and intracranial manifestations of AIFS were included. An iterative review process was utilized in accordance with EBRR guidelines. Levels of evidence and recommendations on management principles for AIFS were generated., Results: A review and evaluation of published literature was performed on 12 topics surrounding AIFS (signs and symptoms, laboratory and microbiology diagnostics, endoscopy, imaging, pathology, surgery, medical therapy, management of extrasinus extension, reversing immunosuppression, and outcomes and survival). The aggregate quality of evidence was varied across reviewed domains., Conclusion: Based on the currently available evidence, judicious utilization of a combination of history and physical examination, laboratory and histopathologic techniques, and endoscopy provide the cornerstone for accurate diagnosis of AIFS. In addition, AIFS is optimally managed by a multidisciplinary team via a combination of surgery (including resection whenever possible), antifungal therapy, and correcting sources of immunosuppression. Higher quality (i.e., prospective) studies are needed to better define the roles of each modality and determine diagnosis and treatment algorithms., (© 2023 ARS-AAOA, LLC.)

Purpose: To identify risk factors for the development of new-onset, postoperative diplopia following orbital decompression surgery based on patient demographics, clinical exam characteristics, radiographic parameters, and surgical techniques., Methods: We conducted a multi-center retrospective chart review of patients who underwent orbital decompression for thyroid eye disease (TED). Patient demographics, including age, gender, smoking history, preoperative exophthalmometry, clinical activity score (CAS), use of peribulbar and/or systemic steroids, and type of orbital decompression were reviewed. Postoperative diplopia was determined at a minimum of 3 months postoperatively and before any further surgeries. Cross-sectional area ratios of each extraocular muscle to orbit and total fat to orbit were calculated from coronal imaging in a standard fashion. All measurements were carried out using PACS imaging software. Multivariable logistic regression modeling was performed using Stata 14.2 (StataCorp, College Station, TX)., Results: A total of 331 patients without preoperative diplopia were identified. At 3 months postoperatively, 249 patients had no diplopia whereas 82 patients developed diplopia. The average postoperative follow-up was 22 months (range 3-156) months. Significant preoperative clinical risk factors for postoperative diplopia included older age at surgery, proptosis, use of peribulbar or systemic steroids, elevated clinical activity score, and presence of preoperative compressive optic neuropathy. Imaging findings of enlarged cross-sectional areas of each rectus muscle to the overall orbital area also conferred a significant risk of postoperative diplopia. Regarding surgical factors, postoperative diplopia was more common among those undergoing medial wall decompression, bilateral orbital surgery, and balanced decompression, whereas endoscopic medial wall decompression was found to be relatively protective., Conclusions: This study identifies risk factors associated with the development of diplopia following orbital decompression using multivariable data. This study demonstrates that several characteristics including age, clinical activity score, the cross-sectional muscle to orbit ratios, in addition to the type of orbital decompression surgery, are predictive factors for the development of new-onset postoperative diplopia., Competing Interests: D.O.K. and B.S.K. Consultant for Horizon Therapeutics. The other authors have no conflicts of interest to disclose., (Copyright © 2022 The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc.)

The authors describe a rare presentation of invasive fungal rhino-orbital cellulitis caused by Saksenaea vasiformis in an immunocompetent child. The patient was initially diagnosed and treated as Mucoraceae , which has a high mortality rate and is primarily seen in immunocompromised patients. Though of the same order, Mucorales, the families Mucoraceae and Saksenaeacae , may be difficult to differentiate on histologic examination and must be distinguished by fungal culture and speciation. Our patient responded well to sino-orbital debridement and systemic treatment with amphotericin and posaconazole.

An 84-year-old male with previously documented poor medical follow-up presented with progressive painless proptosis of the right eye. Right upper eyelid ptosis, limited motility, proptosis, and inferomedial displacement of the right globe were noted on the exam. Computed tomography (CT) imaging revealed a right retrobulbar extraconal heterogenous mass with ill-defined borders. Biopsy revealed a malignant adenocarcinoma with tumor markers suggestive of a colorectal primary. A rectal mass was identified during a systemic workup. After biopsy, the patient was diagnosed with stage IV metastatic rectal adenocarcinoma. He began palliative radiation therapy shortly following diagnosis.

Purpose : To evaluate outcomes of primary eyelid and canalicular laceration repair using a self-retaining bicanalicular hydrophilic nasolacrimal stent. Methods : This study is a retrospective review of seven patients with canalicular laceration primarily repaired with a self-retaining bicanalicular nasolacrimal stent within 72 hours of initial injury. After lacrimal intubation, repair was performed by reapproximation of the lacerated tissues. Data collection included ophthalmic examination, mechanism of injury, involvement of upper/lower/common canaliculi, symptoms of epiphora, operative time, stent extrusion and canalicular irrigation. Results : Seven patients with monocanalicular laceration were repaired using the self-retaining bicanalicular nasolacrimal stent. The stent was left in place an average of 5 months. The average operative time was 29.3 minutes. None of the stents extruded prior to removal. After 5 months, the stent was removed successfully without difficulty. All patients reported subjective improvement in epiphora, with complete resolution of symptoms. Anatomic success was confirmed with irrigation in all cases. There were no complications associated with usage of the self-retaining bicanalicular nasolacrimal stent. Conclusions : Primary repair of canalicular lacerations can be successfully performed with a self-retaining bicanalicular nasolacrimal stent. This stent has several advantages, including potentially faster operative times, no need for intranasal fixation or retrieval, easier intubation in the lacrimal system, and improved anatomic reapproximation of lacerated tissues.

Purpose: Uveal melanomas are associated with characteristic genetic changes. Germline mutations in mismatch repair (MMR) genes and microsatellite instability have been implicated in the development of numerous malignant neoplasms such as colon and ovarian cancers. The frequency of MMR defects in uveal melanomas has yet to be determined., Methods: Here, we analyzed the frequency of MMR gene mutations in uveal melanoma specimens from the University of California, San Diego (UCSD), The Cancer Genome Atlas (TGCA), and the Catalogue of Somatic Mutations in Cancer (COSMIC)., Results: We identified only two mutations in a MMR gene: one premature stop codon in the PMS gene within the UCSD cohort (0.5% frequency) and one in-frame deletion in MSH3 within the COSMIC database (0.8% frequency). We report copy number variation of MLH1 in monosomy 3 and show decreased mRNA expression of MLH1 in uveal melanoma specimens with monosomy 3. Expression levels of MLH1 were not found to correlate with the observed number of total mutations., Conclusion: Overall, we show that mutations in MMR genes in uveal melanoma specimens are exceedingly rare, and although one copy of MLH1 is lost in monosomy 3, it does not seem to have pathologic consequences in uveal melanoma pathogenesis.

Purpose: To assess the recurrence rate of involutional entropion in patients treated with a combined approach including a modified Bick procedure, excision of preseptal orbicularis muscle, and conservative resection of prolapsed orbital fat., Methods: A retrospective chart review of patients undergoing repair of involutional entropion with the combined procedure including orbital fat resection and a second group with standard entropion repair without orbital fat resection was performed. Only patients with follow-up greater than 6 months were included in the study., Results: Seventy eyelids of 54 patients met all inclusion criteria for the combined procedure group over a 9-year period from 2008 to 2016. Average follow-up was 46.9 months. There was a documented recurrence of entropion in 1 eyelid during the follow-up period (1.4%). The remaining 69 cases had successful subjective and objective results without need for any additional procedures. In the group undergoing entropion repair without fat resection, 22 eyelids of 19 patients had the required follow-up period with a recurrence rate of 4.5% (p > 0.05)., Conclusions: The authors demonstrate good surgical success with a combined approach of a modified Bick procedure, preseptal orbicularis excision, and conservative orbital fat resection. Conservative fat resection during entropion repair was found to be safe, and the combined procedure was found to be effective with a rate of recurrent entropion of 1.4% on extended follow-up.The authors propose that orbital fat prolapse contributes to the mechanics of involutional entropion and that conservative orbital fat resection during surgical repair of entropion can be done safely, resulting in low recurrence rates.

Purpose: To examine the role of adjuvant surgical resection of infantile hemangiomas after systemic β-blocker therapy., Methods: This is a multicentered retrospective study. Standard protocol for oral propranolol was employed by the referring physicians. Ocular indications for surgery included ptosis obstructing the visual axis, high degrees of astigmatism causing amblyopia, or disfigurement from residual tumor. Patients underwent complete excision or debulking., Results: Eleven girls and 4 boys were surgically treated with mean operative age of 34.4 months. Patients were followed for a mean of 19.6 months after surgery. Four patients required surgical treatment due to an inability to tolerate medical therapy secondary to drug-related side effects (including bradycardia). The other 11 patients proceeded to surgery due to residual eyelid and orbital lesions despite medical treatment. All 15 patients underwent orbitotomy for residual hemangioma excision. Four patients also underwent simultaneous levator advancement at the time of excision. In all cases, there was resolution of ptosis with clearing of the visual axis. No complications were incurred during the surgical treatment and there were no hemangioma recurrences., Conclusions: This is the first study to report surgical management of periocular infantile hemangiomas recalcitrant to standard therapy in the β-blocker era. In patients with infantile hemangioma who have failed medical therapy, adjuvant surgical treatment still plays an important role. For patients with persistent tumor causing ocular sequelae, surgical intervention aimed at soft tissue debulking and ptosis repair can be successful in achieving excellent functional and aesthetic outcomes with minimal side effects.For patients with periocular infantile hemangiomas with residual soft tissue deformity following propranolol therapy, surgical treatment plays an important role in improving functional and cosmetic outcomes with minimal side effects.

The authors describe a clinical case whereby a patient with metastatic cutaneous melanoma developed eyelash poliosis after undergoing treatment with combination immunotherapy with ipilimumab and nivolumab.

Purpose: To evaluate the efficacy in degree of ptosis correction achieved by single suture Müeller muscle conjunctival resection (ssMMCR) when compared with that of traditional MMCR., Methods: A retrospective chart analysis of patients who underwent either ssMMCR or traditional MMCR at 2 institutions. Single suture MMCR was performed after using a ptosis clamp to imbricate conjunctiva and Müeller muscle. Margin-to-reflex distance 1 was measured pre- and postoperatively, and the change in margin-to-reflex distance 1 was analyzed for both groups. Patients were monitored in follow up for postoperative complications including lagophthalmos, corneal abrasions, and change in visual acuity. Statistical analysis was performed using the Microsoft Excel and Stata software programs., Results: Twenty-seven and 30 patients underwent single suture and traditional MMCR, respectively. The ssMMCR and MMCR groups were followed postoperatively for approximately 4.2 and 9.7 months, respectively and the average margin-to-reflex distance 1 increased by 2.93 mm and 2.81 mm, respectively. Notably, there was no statistically significant difference in the means identified by t test. Of the 94 eyelid surgeries evaluated, 1 ssMMCR and 3 MMCR eyelids required further surgical revision for persistent ptosis, and 1 ssMMCR developed a transient corneal epithelial abrasion. Surgical revisions were rare with both procedures, and patient satisfaction was high., Conclusions: Single suture MMCR is an efficient and effective method for ptosis repair. It results in comparable outcomes including elevation in margin-to-reflex distance 1, safety profile, and reoperation rates, when compared with traditional MMCR.

Purpose: To report the ocular and adnexal injuries sustained by patients with Thomas A. Swift's electric rifles (TASER; TASER International, Scottsdale, AZ), review the literature, and discuss the management of this complex trauma., Design: Multicenter, retrospective case series and literature review., Participants: Seventeen eyes of 16 patients (5 eyes of 5 patients treated at 3 institutions, and 12 eyes of 11 previously reported cases)., Methods: The clinical data of 17 eyes were pooled. Spearman's correlation coefficient was used to assess the association between the extent of TASER injury and patient outcomes., Main Outcome Measures: Extent of TASER injury (zone of injury, penetrating vs. perforating) and association with patient outcomes (visual acuity [VA] and retinal detachment [RD])., Results: In our cohort, 4 patients were transported by law enforcement and 1 was transferred from a community hospital. Four patients were taken to the operating room for TASER removal and globe repair; 1 patient underwent removal in the emergency room. Of 17 pooled cases, 12 (71%) involved open-globe injury. Of these, there was a high rate of zone 3 injuries (100%; n = 12) and a high incidence of RD (73%; 8 of 11, eviscerated eye excluded). Among patients with closed-globe injury (n = 5), 1 patient demonstrated exudative RD and 1 patient demonstrated retinal dialysis with RD. Of 10 patients with RD, 1 (10%) achieved resolution with monitoring (exudative RD); 1 (10%) underwent cryopexy and pneumatic retinopexy; 3 (30%) underwent vitrectomy, and 5 (50%) with poor prognosis did not undergo vitreoretinal surgery. In the 3 patients who underwent vitrectomy, all 3 (100%) demonstrated redetachment resulting from proliferative vitreoretinopathy and required additional surgery. Visual acuity on presentation was significantly correlated with final VA (ρ = 0.783; P = 0.02). Men (94%) were more likely than women (6%) to sustain TASER trauma. Median age was 26 years. There was a 50% rate of loss to follow-up., Conclusions: Thomas A. Swift's electric rifle injuries to the eyes or ocular adnexa represent complex trauma. Zone 3 injuries are common. The visual prognosis is guarded, and eyes may require multiple surgeries to preserve vision. Patients are at high risk for loss to follow-up by way of incarceration., (Copyright © 2018 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: To describe historical and modern surgical approaches to orbital decompression in patients with thyroid-related orbitopathy in the quiescent phase., Methods: A literature review of published techniques using the National Institutes of Health PubMed database., Results: Historically, orbital decompression has been accomplished via transantral, transcranial, transnasal, and orbital approaches. Current techniques use predominately periocular incisions to achieve effective decompression and proptosis reduction. Based on exophthalmometry and desired proptosis reduction, the authors propose a graded surgical approach to decompression for thyroid orbitopathy beginning with fat reduction, followed by deep lateral orbit via a superior eyelid crease incision, then medial wall by retro-caruncular approach, then posterior medial orbital floor either via transconjunctival or swinging eyelid approach, and finally with lateral orbital rim removal by superior eyelid crease incision as needed. These approaches can result in a range of proptosis reduction of up to 10 mm., Conclusions: A structured approach to orbital decompression results in predictable and effective outcomes in proptosis reduction.

Purpose: To evaluate the efficacy of intravenous immunoglobulin in the treatment of cystoid macular edema and uveitis caused by juvenile retinitis pigmentosa in a woman interested in planning a pregnancy., Methods: Descriptive case report. A 25-year-old woman with retinitis pigmentosa presented with decreased visual acuity, interested in a second opinion., Results: Intravenous immunoglobulin therapy was begun at 2-week intervals. Visual acuity improved from 20/100 to 20/70 by 6 weeks, where it stabilized for the remaining year. Serial optical coherence tomography imaging revealed marked improvement in cystoid macular edema after 2 treatments of intravenous immunoglobulin at 2 weeks of follow-up, with complete resolution noted at 4 months, a finding that persisted at 1 year of follow-up., Conclusion: Our findings support the use of intravenous immunoglobulin as a therapeutic option for the resolution of cystoid macular edema and management of uveitis secondary to juvenile retinitis pigmentosa.

Gorham-Stout disease (GSD) is a rare angiomatous disorder characterized by osteolysis. We report the case of a 66-year-old woman who developed sudden left eye proptosis and facial pain. Neuroimaging demonstrated a destructive mass involving the roof and lateral wall of the left orbit with adjacent abnormal orbital soft tissue. An initial biopsy of the soft tissue was nondiagnostic; however, transcranial biopsy of the orbital roof revealed an intraosseous cavernous angioma, with infiltration of orbital fat by angiomatous tissue. Despite resection of the orbital roof and lateral wall, the orbital lesion continued to expand, leading to signs of a compressive optic neuropathy. The patient then reported severe back pain, prompting imaging that demonstrated disseminated bony involvement of the axial skeleton, eventually leading to the diagnosis of GSD. The patient was treated with a bisphosphonate and a vascular endothelial growth factor inhibitor with stabilization of disease.

Purpose: To investigate the pathogens and biofilms responsible for clinically significant infection of silicone stents implanted within the lacrimal system., Methods: Retrospective review of culture results and patient demographics for all silicone lacrimal stents removed early for clinically significant infection and sent to the Bascom Palmer Microbiology Laboratory through the end of year 2010. As a control, routinely removed, clinically noninfected stents from the same institution were prospectively sent for culture over a 6-month period. Four clinically infected and 6 clinically noninfected stents showing mucus within the lumen at removal were sent for scanning electron microscopy. Images were randomized and graded by a microbiologist for the presence of organisms, matrix deposits, organisms within matrix, and overall impression of significant biofilm formation., Results: Nineteen stents were included in the study; 100% of clinically infected (n = 10) and noninfected (n = 9) stents were culture positive. Culture positivity for nontuberculous mycobacterium was found in 90% of infected stents and none of the noninfected stents (p < 0.001). Of infected stents, 50% grew Gram-positive organisms compared with 89% of noninfected stents (p = 0.07). Fifty percent of infected versus 67% of noninfected stents were culture positive for Gram-negative organisms (p = 0.46). Electron microscopy of stents revealed organisms consistent with culture results (size, shape) in planktonic and biofilm form. Masked observer image grading revealed a statistically significant higher amount of organism and biofilm on infected versus noninfected specimen., Conclusion: Nontuberculous mycobacteria comprise the primary pathogens responsible for clinically significant infection of silicone stents in the lacrimal system in South Florida. Robust biofilm production by this organism likely plays a role in pathogenesis. Further research into biofilm-related lacrimal implant infection may aid in the development of useful prevention and treatment strategies.

Purpose: To describe a case series of transient oxygen desaturation measured by pulse oximetry during the intravenous infusion of indocyanine green to enhance transpupillary thermotherapy in treating retinoblastoma after ophthalmic artery chemosurgery., Methods: Retrospective descriptive case series., Results: The intravenous administration of indocyanine green for ophthalmic angiography resulted in a transient drop in oxygen saturation as measured by Nellcor fingertip pulse oximetry in three children with retinoblastoma receiving indocyanine green-guided transpupillary thermotherapy. The magnitude of reduction ranged from 92% to 94% from an initial reading of 99% to 100% in each case, with an average duration of 3 minutes. Concurrent measurement of blood pressure, pulse, and expired CO2 showed no changes during this process., Conclusion: Administration of intravenous indocyanine green resulted in a transient desaturation by oximetry during transpupillary thermotherapy for children with retinoblastoma under anesthesia because of the fluorescent dye's absorption of red light in a manner similar to that of deoxygenated hemoglobin, thereby leading to transient instrument misinterpretation and miscalculation of arterial oxygenation.

A 67-year-old gentleman presented to Yale-New Haven Hospital (YNHH) for assessment of a supratherapeutic INR and sacral lesion. Hematologic workup revealed elevated ESR, PT, INR, PTT, and CRP, mixing studies that failed to correct, and a positive Russell Viper Venom Test (RVVT), which confirmed the presence of lupus anticoagulant (LA), a subtype of antiphospholipid syndrome (APA). Pathology of the patient's sacral lesion revealed diffuse large B-cell lymphoma. This case provides insight into the association between APA and lymphoid neoplasm. The patient's unique presentation is in marked contrast to other reports of APA and lymphoid malignancy, which are typically associated with elevated PTT, normal PT, minimal extranodal disease, and potential thrombotic complications. Further, treatment with Rituximab-CHOP chemotherapy led to excellent clinical response with tumor remission and normalization of PT and PTT.

ABCG2 is an ATP-binding cassette half-transporter initially identified in multidrug-resistant cancer cell lines and recently suggested to play an important role in pharmacokinetics. Here we report studies of a conserved arginine predicted to localize near the cytoplasmic side of TM1. First, we determined the effect of losing charge and bulk at this position via substitutions with glycine and alanine. The R383G mutant when transfected into HEK cells was not detectable on immunoblot or by functional assay, while the R383A mutant exhibited detectable but significantly decreased levels compared to wild-type, partial retention in the ER and altered glycosylation. Efflux of the ABCG2-substrates mitoxantrone and pheophorbide a was observed. Our experiments suggested rapid degradation of the R383A mutant by the proteasome via a kifunensine-insensitive pathway. Interestingly, overnight treatment of the R383A mutant with mitoxantrone assisted in protein maturation as evidenced by a shift to the N-glycosylated form. The R383A mutant when expressed in insect cells, though detected on the surface, had no measurable ATPase activity. In addition, substitution with the positively charged lysine resulted in significantly decreased protein expression levels in HEK cells, while retaining function. In conclusion, arginine 383 is a crucial residue for ABCG2 biogenesis, where even the most conservative mutations have a large impact.

ABCG2 is a half-transporter initially described in multidrug-resistant cancer cells and lately identified as an important factor in the pharmacokinetics of its substrates. Q141K is by far the most intensively studied single nucleotide polymorphism of ABCG2 with potential clinical relevance. Here we used stably transfected HEK cells to study the Q141K polymorphism together with the deletion of amino acids 315-316, which were recently reported to coexist in two cancer cell lines (A549 and SK-OV-3). Functional studies confirmed our previous report that when normalized to surface expression, Q141K has impaired transport of mitoxantrone. This result was extended to include the ABCG2-specific substrate pheophorbide a. While we found no functional consequence of deleting amino acids 315 and 316, we did find that the deletion mutant is no longer recognized by the BXP-21 antibody. We conclude that amino acids 315 and 316 form part of the epitope for the BXP-21 antibody.