Vitreous metastasis from cutaneous melanoma: diagnosis and management / Metástase vítrea de melanoma cutâneo: diagnóstico e tratamento

ABSTRACT Purpose: To report the clinical findings, treatments, and outcomes in a series of patients with vitreous metastasis from cutaneous melanoma. Methods: This single-center, retrospective, interventional case series included patients with biopsy-confirmed vitreous metastasis from cutaneous melanoma diagnosed between 1997 and 2020. Standard 23- or 25-gauge pars plana vitrectomy was performed for diagnostic sampling. Sclerotomies were treated with double or triple freeze-thaw cryotherapy. Perioperative intravitreal injections of melphalan (32 µg/0.075 mL) were administered, when indicated. Visual acuity, intraocular pressure, and systemic and ocular treatment responses were reported. Results: Five eyes of five patients with unilateral vitreous metastasis from cutaneous melanoma were identified. The median age at diagnosis was 84 (range, 37-88) years. The median follow-up after ophthalmic diagnosis was 28 (8.5-36) months; one patient did not have a follow-up. The initial visual acuity ranged from 20/30 to hand motions. Baseline clinical findings included pigmented or non-pigmented cellular infiltration of the vitreous (5/5), anterior segment (4/5), and retina (3/5). Four patients had secondary glaucoma. Systemic therapy included checkpoint inhibitor immunotherapy (n=3, all with partial/complete response), systemic chemotherapy (n=2), surgical resection (n=3), and radiation (n=2). The median time from primary diagnosis to vitreous metastasis was 2 (2-15) years. One patient had an active systemic disease at the time of vitreous metastasis. The final visual acuity ranged from 20/40 to no light perception. Ophthalmic treatment included vitrectomy in all five patients, intravitreal administration of melphalan in three, and intravitreal administration of methotrexate in one. One patient required enucleation, and histopathology revealed extensive invasion by melanoma cells. Conclusions: Vitreous metastasis from cutaneous melanoma can present as a diffuse infiltration of pigmented or non-pigmented cells into the vitreous and may be misdiagnosed as uveitis. Diagnostic pars plana vitrectomy and periodic intravitreal chemotherapy may be indicated.

RESUMO Objetivo: Descrever os achados clínicos, tratamentos, e desfechos em uma série de pacientes com me tástases vítreas de melanoma cutâneo. Métodos: Série retrospectiva de casos de único centro com intervenção. Pacientes incluídos tiveram seu diagnóstico de MVMC confirmado por biópsia entre 1997 e 2020. Vitrectomia via pars plana com 23 ou 25 gauge foram realizadas para obter espécimens. Esclerotomias foram tratadas com crioterapia em duplo ou triplo congelamento. Injeção intravítrea perioperatória de melfalano (32 ug/0,075 mL) foi administrada quando necessário. Foram relatados acuidade visual, pressão intraocular, resposta terapêutica sistêmica e ocular. Resultados: Cinco olhos de 5 pacientes com metástases vítreas de melanoma cutâneo unilateral foram identificados. Idade média de diagnóstico foi 84 anos (variando de 37-88). Seguimento médio após diagnóstico oftalmológico foi 28 (8,5-36) meses; 1 paciente não teve acompanhamento. Acuidade visual inicial variou de 20/30 a movimentos de mão. Achados clínicos iniciais incluíram infiltração de células pigmentadas e não-pigmentadas no vítreo (5/5), segmento anterior (4/5), e retina (3/5). Quatro pacientes tiveram glaucoma secundário. Tratamento sistêmico incluiu imunoterapia com inibidores da via de sinalização (3 - todos com resposta parcial/completa), quimioterapia sistêmica (2), ressecção cirúrgica (3), e irradiação (2). Intervalo médio entre diagnóstico primário e metástases vítreas foi 2 (2-15) anos. Um paciente teve doença sistêmica ativa simultânea as metástases vítreas. Acuidade visual final variou entre 20/40 e SPL. Tratamento oftalmológico incluiu vitrectomia nos 5 pacientes, melfalano intravítreo em 3 e metotrexato intravítreo em 1. Um paciente precisou de enucleação. A histopatologia revelou invasão celular extensa de melanoma. Conclusões: Metástases vítreas de melanoma cutâneo pode se manifestar como uma infiltração difusa de células pigmentadas e não-pigmentadas no vítreo e erroneamente diagnosticada como uveites. Vitrectomia diagnóstica e quimioterapia intravítrea periódica podem estar indicadas.

Outcomes and complications of primary rhegmatogenous retinal detachment repair with pars plana vitrectomy in young adults.

BACKGROUND: Scleral buckling has been the standard for rhegmatogenous retinal detachment repair in young patients given the typical lack of posterior vitreous detachment, phakic status, and lower risk of proliferative vitreoretinopathy. In older patients, pars plana vitrectomy alone is typically used for rhegmatogenous retinal detachment repair. We report the outcomes and complications of pars plana vitrectomy for rhegmatogenous retinal detachment in young eyes. METHODS: Retrospective, single-center cohort study. Medical records of patients between 15 to 45 years of age undergoing primary pars plana vitrectomy for rhegmatogenous retinal detachment repair between 2010 and 2020 were carefully reviewed. All analyses were performed using the Kruskal-Wallis tests for numeric covariates between age groups. RESULTS: Eyes were stratified by age: 15-24 (group 1, n = 10), 25-34 (group 2, n = 14), and 35-45 (group 3, n = 38). The average number of surgeries were 1.9, 1.4, and 1.1 in groups 1, 2, and 3, respectively (p = 0.004). Single surgery success rates were 50%, 64%, and 92% in groups 1, 2 and 3, respectively (p = 0.005). Final reattachment rates were 80%, 93%, 100% in groups 1, 2, and 3, respectively (p = 0.568). Proliferative vitreoretinopathy developed in 50%, 7%, and 8% of eyes in groups 1, 2, and 3, respectively (p < 0.001). CONCLUSION: While the final reattachment rates were excellent in all groups, the higher rates of proliferative vitreoretinopathy and lower single surgery success rate in younger patients may suggest that primary pars plana vitrectomy may not be the optimal repair method in these age groups.

CHRONIC PEDIATRIC RETINAL DETACHMENT WITH MULTIPLE MACROCYSTS.

PURPOSE: To describe a case of chronic pediatric retinal detachment with multiple macrocysts, its surgical management, and a review of the literature. METHODS: Case report with fundus photography and optical coherence tomography. RESULTS: We describe a case of an asymptomatic, 11-year-old boy with a chronic rhegmatogenous retinal detachment with multiple peripheral macrocysts. The patient had counting fingers visual acuity on presentation. The detachment was successfully surgically repaired with scleral buckling, subretinal fluid drainage, cryotherapy, and a SF6 tamponade. At the 12-month follow-up, the retina remained attached with improvement of visual acuity to 20/100 with resolution of the cysts. Optical coherence tomography revealed loss of macular ellipsoid zone. Genetic testing revealed a heterozygous dominant COL11A1 mutation. CONCLUSION: To the authors' knowledge, this is the first reported case of chronic retinal detachment presenting with multiple peripheral macrocysts in a pediatric patient with Stickler syndrome. More research is needed into the cause and significance of retinal macrocysts, particularly in the pediatric population.

Visual barcodes for clonal-multiplexing of live microscopy-based assays.

While multiplexing samples using DNA barcoding revolutionized the pace of biomedical discovery, multiplexing of live imaging-based applications has been limited by the number of fluorescent proteins that can be deconvoluted using common microscopy equipment. To address this limitation, we develop visual barcodes that discriminate the clonal identity of single cells by different fluorescent proteins that are targeted to specific subcellular locations. We demonstrate that deconvolution of these barcodes is highly accurate and robust to many cellular perturbations. We then use visual barcodes to generate 'Signalome' cell-lines by mixing 12 clones of different live reporters into a single population, allowing simultaneous monitoring of the activity in 12 branches of signaling, at clonal resolution, over time. Using the 'Signalome' we identify two distinct clusters of signaling pathways that balance growth and proliferation, emphasizing the importance of growth homeostasis as a central organizing principle in cancer signaling. The ability to multiplex samples in live imaging applications, both in vitro and in vivo may allow better high-content characterization of complex biological systems.

Squamoid Eccrine Ductal Carcinoma of the Eyelid: Clinicopathologic Correlation of a Case.

Squamoid eccrine ductal carcinoma (SEDC) is a rare cutaneous neoplasm that often manifests as a plaque or nodule in sun-exposed areas of older patients. Herein, the authors report the first case of SEDC in the eyelid. A 76-year-old man presented with a 2.5 × 1.5 mm area of left upper eyelid erythema, thickening, ulceration, and scaling with madarosis superotemporally just above the lash line. Full-thickness wedge biopsy demonstrated irregular epithelial tubules with nuclear atypia and focal squamous differentiation, consistent with SEDC. The patient underwent Mohs resection and has had no recurrence approximately 27 months after surgical removal. The authors present this case to raise awareness of SEDC to ophthalmologists as all previous cases have been described in the nonophthalmic literature. A full-thickness biopsy is recommended to avoid misdiagnosing SEDC as squamous cell carcinoma (SCC), a less aggressive tumor. With greater awareness, there may be increased recognition of this likely underreported, more malignant entity.

Metastatic Uterine Carcinosarcoma to the Orbit.

Metastases of solid tumors to the eye and ocular adnexa are rare. Herein, the authors describe the clinical, histologic, and immunohistochemical findings of a patient with a history of adenocarcinoma of the colon and a uterine carcinosarcoma (malignant mixed Müllerian tumor) who presented with proptosis and decreased vision. Positive staining with PAX-8, p16 and negative reaction for CK20 and CDX2 helped to establish the uterine origin of the metastasis. This rare case demonstrates the utility of immunohistochemical probes, especially in patients with a complex oncological history, where multiple primary sources of the metastasis are in the differential diagnosis.

Brolucizumab-related retinal vasculitis with exacerbation following ranibizumab retreatment: A clinicopathologic case study.

PURPOSE: To describe the clinical and pathologic characteristics of a case of retinal vasculitis and vitritis following brolucizumab administration and subsequent ranibizumab treatment. OBSERVATIONS: A 76-year old Caucasian woman experienced pain, decreased vision and floaters one week after receiving her third monthly intravitreal brolucizumab injection in the right eye for exudative age-related macular degeneration. Examination was significant for 0.5+ anterior chamber cells, vitritis, mild peripheral vascular sheathing, and decreased vision from 20/70 to 20/200. She was started on topical 1% prednisolone acetate with improvement in her examination. She was switched to ranibizumab one month after her last brolucizumab injection of the right eye. Three weeks after her ranibizumab injection, she noticed photophobia, pain and decreased vision. Examination revealed worsening uveitis, vitritis, vascular sheathing, and decreased vision to count fingers. Despite starting on 0.05% difluprednate drops every 2 hours and oral high-dose methylprednisolone, the patient did not have any significant improvement in her symptoms or examination. She underwent pars plana vitrectomy and vitreous biopsy with intravitreal triamcinolone injection to the right eye. Vitreous biopsy and culture ruled out infectious endophthalmitis, and further cytopathologic analysis revealed chronic inflammatory infiltrate. CONCLUSION AND IMPORTANCE: Treatment with brolucizumab can result in intraocular inflammation and retinal vasculitis likely due to a delayed hypersensitivity reaction to the drug, supported by cytopathologic analysis of a vitreous sample. We demonstrate a case where retreatment with an alternative anti-VEGF agent resulted in worsening vision and vasculitis.

Clinical Diagnosis and Histopathologic Features of a Synthetic Fiber Granuloma.

The authors report a case of a synthetic fiber granuloma to demonstrate the challenges in diagnosing these lesions and to highlight their histopathologic features. This is the first report in the literature to use histopatho-logic and immunofluorescence studies to characterize the subtype and distribution of macrophages in synthetic fiber granuloma. [J Pediatr Ophthalmol Strabismus. 2020;57:e92-e95.].

Chloride intracellular channel 1 cooperates with potassium channel EAG2 to promote medulloblastoma growth.

Ion channels represent a large class of drug targets, but their role in brain cancer is underexplored. Here, we identify that chloride intracellular channel 1 (CLIC1) is overexpressed in human central nervous system malignancies, including medulloblastoma, a common pediatric brain cancer. While global knockout does not overtly affect mouse development, genetic deletion of CLIC1 suppresses medulloblastoma growth in xenograft and genetically engineered mouse models. Mechanistically, CLIC1 enriches to the plasma membrane during mitosis and cooperates with potassium channel EAG2 at lipid rafts to regulate cell volume homeostasis. CLIC1 deficiency is associated with elevation of cell/nuclear volume ratio, uncoupling between RNA biosynthesis and cell size increase, and activation of the p38 MAPK pathway that suppresses proliferation. Concurrent knockdown of CLIC1/EAG2 and their evolutionarily conserved channels synergistically suppressed the growth of human medulloblastoma cells and Drosophila melanogaster brain tumors, respectively. These findings establish CLIC1 as a molecular dependency in rapidly dividing medulloblastoma cells, provide insights into the mechanism by which CLIC1 regulates tumorigenesis, and reveal that targeting CLIC1 and its functionally cooperative potassium channel is a disease-intervention strategy.

Trends and Outcomes of Intravascular Imaging-guided Percutaneous Coronary Intervention in the United States.

INTRODUCTION: Intravascular imaging-guided percutaneous coronary intervention (PCI) has shown to improve outcomes in randomized controlled trials. However, there are little real-world data about intravascular imaging utilization during PCI and its outcomes in the United States. METHODS: We conducted an observational analysis on the use of intravascular imaging (Intravascular Ultrasound or Optical Coherence Tomography)-guided PCI in 2,425,036 patients undergoing PCI between January 2010 and December 2014 from the Nationwide Inpatient Sample database. Utilizing propensity score matching, 83,988 matched pairs were identified. The primary outcome was in-hospital mortality. The secondary outcomes included cardiogenic shock and acute kidney injury. RESULTS: Among the 2,425,036 patients, 161,808 (6.7%) underwent imaging-guided PCI. Use of imaging-guidance increased from 6% in 2010 to 6.6% in 2014 (Ptrend < 0.001). The in-hospital mortality was significantly different between imaging-guided PCI and angiography-guided PCI [1.0% vs. 1.5%; adjusted OR: 0.67; 95% confidence interval (CI): 0.54-0.83, P < 0.001]. The rates of cardiogenic shock (2.5% vs. 3.1%; adjusted OR: 0.78; 95% CI: 0.66-0.93; P = 0.005) were significantly lower in imaging-guided PCI group and acute kidney injury rates (7.0% vs. 7.1%; adjusted OR: 0.99; 95% CI: 0.89-1.12; P = 0.919) were not significantly different. CONCLUSIONS: Imaging-guided PCI is associated with lower in-hospital mortality. Yet, a small proportion of patients undergoing PCI have imaging-guidance.

Identification of population characteristics through implementation of the Comprehensive Diabetic Retinopathy Program.

BACKGROUND: Diabetic retinopathy is the most common cause of blindness in working-age adults. Characteristics of patients with diabetes presenting to a retina subspecialty clinic have not been adequately studied, limiting our ability to risk stratify patients with diabetic retinopathy. Our goal is to describe an innovative program that collects structured, longitudinal data on patients with diabetes in a retina clinic, and identifies population characteristics to define patient risk stratification. METHODS: Demographics, body-mass index, blood pressure, hemoglobin A1c, smoking history, diabetes type, diabetes duration, kidney disease history, and diagnosis codes were collected on all patients with diabetes at the Kellogg Eye Center retina clinic. A mixed effects negative binomial regression was then performed to assess visit frequency as a function of these variables. Visit frequency was used as a marker for cost of care. A subgroup of patients was surveyed about knowledge of diabetes management goals and barriers to better self-management. RESULTS: There were 2916 patients in the cohort with 1014 in the subgroup. The cohort was predominantly Caucasian (74.5%), with a mean age of 64 years (range 13-99) and a relatively even distribution of sex (53.2% men). The mean maximum hemoglobin A1c was 8.0% (range 4.3-15.7%), and 57.1% had a diagnosis of diabetic retinopathy. Patients averaged 3.9 visits (range 1-27) during the 18-month study period. Blood pressure and duration of diabetes were positively associated with visit frequency (p < 0.0001, p < 0.0001, respectively). Of the surveyed patients, 87.6% knew their goal hemoglobin A1c, while only 45.9% identified the correct blood pressure goal. The most common reported barrier to better self-management was "it's just not working" (47.1%). CONCLUSIONS: Implementation of this program enables the creation of a longitudinal dataset on patients with diabetes. Resulting data can be used to improve quality of care provided to patients at a retina clinic. The findings suggest considerable healthcare resources are being directed to a small patient population. This enhanced understanding of characteristics of patients with diabetes will improve efforts to preserve vision and utilize health system resources efficiently.

Longitudinal Examination of Fellow-Eye Vascular Anomalies in Coats' Disease With Widefield Fluorescein Angiography: A Multicenter Study.

BACKGROUND AND OBJECTIVE: Retinovascular anomalies in the fellow eyes of patients with Coats' disease have been described, but the clinical significance is unknown, as well as whether these lesions progress over time. PATIENTS AND METHODS: This is an international, multicenter, retrospective, observational cohort study of fellow-eye abnormalities on widefield fluorescein angiography in patients with Coats' disease. RESULTS: Three hundred fifty eyes of 175 patients with Coats' disease were analyzed. A total of 33 patients (18.8%) demonstrated abnormal fellow-eye findings: 14 (42.4%) telangiectasias, 18 (54.5%) aneurysms, six (18.2%) segmental non-perfusion, six (18.2%) leakage, and two (6.0%) vascular tortuosity. All eyes were asymptomatic, and none of the lesions progressed over time. There was no association between fellow-eye findings with severity of Coats' disease (P = .16), patient age (P = .16), or presence of systemic vascular disease (P = .16). CONCLUSIONS: The vascular abnormalities in fellow eyes of patients with Coats' disease did not progress over time. Observation is a reasonable initial management strategy. [Ophthalmic Surg Lasers Imaging Retina. 2019;50:221-227.].

Predictors and etiologies of 30-day readmissions in patients with non-ST-elevation acute coronary syndrome.

BACKGROUND: Despite improvements in acute care and survival after non-ST-elevation acute coronary syndrome (NSTE-ACS) hospitalization, early readmissions remain common, and have significant clinical and financial impact. OBJECTIVES: Determine the predictors and etiologies of 30-day readmissions in NSTE-ACS. METHOD: The study cohort was derived from the National Readmission Database 2014 identifying patients with a primary diagnosis of NSTE-ACS using ICD9 code. RESULTS: We identified a total of 300,269 patients admitted with NSTE-ACS; 13.4% were readmitted within 30-day. The most common cause of readmission was heart failure (HF) (15.6%), followed by a recurrent myocardial infarction (MI) (10%). Predictors of increased readmissions were age ≥ 75 years (OR: 1.34, 95% CI: 1.30-1.39), female gender (OR 1.12, 95% CI 1.09-1.16), a Charlson Comorbidity Index (CCI) >3 (OR 2.11, 95% CI: 2.04-2.18), ESRD (OR 2.01, 95% CI 1.89-2.14), CKD (OR: 1.58, 95% CI: 1.51-1.64), length of stay ≥5 days (OR: 1.51, 95% CI 1.46-1.56) and adverse events during the index admission such as AKI (OR:1.31, 95% CI: 1.25-1.36), major bleeding (OR:1.20, 95% CI: 1.12-1.24); whereas admission to a teaching hospital (OR 0.92, 95% CI 0.89-0.95) and PCI (OR 0.70, 95% CI 0.67-0.72) were associated with less likelihood of 30-day readmission. CONCLUSION: Readmission rate at 30-days is high among NSTE-ACS patients and the most common readmission etiologies are HF and recurrent MI. A CCI more than 3 and ESRD were the most significant predictors for readmission; patients undergoing PCI had less odds of readmission.

Cell size sensing in animal cells coordinates anabolic growth rates and cell cycle progression to maintain cell size uniformity.

Cell size uniformity in healthy tissues suggests that control mechanisms might coordinate cell growth and division. We derived a method to assay whether cellular growth rates depend on cell size, by monitoring how variance in size changes as cells grow. Our data revealed that, twice during the cell cycle, growth rates are selectively increased in small cells and reduced in large cells, ensuring cell size uniformity. This regulation was also observed directly by monitoring nuclear growth in live cells. We also detected cell-size-dependent adjustments of G1 length, which further reduce variability. Combining our assays with chemical/genetic perturbations confirmed that cells employ two strategies, adjusting both cell cycle length and growth rate, to maintain the appropriate size. Additionally, although Rb signaling is not required for these regulatory behaviors, perturbing Cdk4 activity still influences cell size, suggesting that the Cdk4 pathway may play a role in designating the cell's target size.

Size uniformity of animal cells is actively maintained by a p38 MAPK-dependent regulation of G1-length.

Animal cells within a tissue typically display a striking regularity in their size. To date, the molecular mechanisms that control this uniformity are still unknown. We have previously shown that size uniformity in animal cells is promoted, in part, by size-dependent regulation of G1 length. To identify the molecular mechanisms underlying this process, we performed a large-scale small molecule screen and found that the p38 MAPK pathway is involved in coordinating cell size and cell cycle progression. Small cells display higher p38 activity and spend more time in G1 than larger cells. Inhibition of p38 MAPK leads to loss of the compensatory G1 length extension in small cells, resulting in faster proliferation, smaller cell size and increased size heterogeneity. We propose a model wherein the p38 pathway responds to changes in cell size and regulates G1 exit accordingly, to increase cell size uniformity.

Temporal Trends, Predictors, and Outcomes of In-Hospital Gastrointestinal Bleeding Associated With Percutaneous Coronary Intervention.

Since the introduction of new antiplatelet and anticoagulant agents in the last decade, large-scale data studying gastrointestinal bleeding (GIB) in patients undergoing percutaneous coronary intervention (PCI) are lacking. Using the Nationwide Inpatient Sample, we identified all hospitalizations from 2006 to 2012 that required PCI. Temporal trends in the incidence and multivariate predictors of GIB associated with PCI were analyzed. A total of 4,376,950 patients underwent PCI in the United States during the study period. The incidence of GIB was 1.1%. Mortality rate in the GIB group was significantly higher (9.71% vs 1.1%, p <0.0001). Although the incidence of GIB remained stable during the study period (0.97% in 2006 to 1.19% in 2012), in-hospital mortality rate increased significantly from 7.9% in 2006 to 10.78% in 2012, with a peak of 12% in 2010. The GIB group had a longer median length of stay (5.80 vs 1.57 days) and an increased median cost of hospitalization ($26,564 vs $16,879). The predictors of GIB included cardiovascular co-morbidities such as acute myocardial infarction, cardiogenic shock, atrial fibrillation, congestive heart failure, valvular heart diseases, and a history of transient ischemic attack/stroke. Gastrointestinal co-morbidities including diverticulosis, esophageal cancer, stomach cancer, small intestine cancer, large intestine cancer, rectosigmoid cancer, gastrointestinal ulcer, and liver disease were predictors of GIB. Interestingly, a lower risk of GIB was associated with obese patients and patients with private insurance. A higher risk of GIB was noted in urgent versus elective admissions and weekend versus weekday admissions. In conclusion, the incidence of GIB in patients who underwent PCI remained stable from 2006 to 2012; however, the in-hospital mortality increased significantly. Identifying patients at higher risk for GIB is critically important to develop preventive strategies to reduce morbidity and mortality.

Identification of prolyl hydroxylation modifications in mammalian cell proteins.

Prolyl hydroxylation is a PTM that plays an important role in the formation of collagen fibrils and in the oxygen-dependent regulation of hypoxia inducible factor-α (HIF-α). While this modification has been well characterized in the context of these proteins, it remains unclear to what extent it occurs in the remaining mammalian proteome. We explored this question using MS to analyze cellular extracts subjected to various fractionation strategies. In one strategy, we employed the von Hippel Lindau tumor suppressor protein, which recognizes prolyl hydroxylated HIF-α, as a scaffold for generating hydroxyproline capture reagents. We report novel sites of prolyl hydroxylation within five proteins: FK506-binding protein 10, myosin heavy chain 10, hexokinase 2, pyruvate kinase, and C-1 Tetrahydrofolate synthase. Furthermore, we show that identification of prolyl hydroxylation presents a significant technical challenge owing to widespread isobaric methionine oxidation, and that manual inspection of spectra of modified peptides in this context is critical for validation.

Targeting HER2+ breast cancer cells: lysosomal accumulation of anti-HER2 antibodies is influenced by antibody binding site and conjugation to polymeric nanoparticles.

Humanized monoclonal antibodies (mAb) against HER2 are being engineered to treat cancer. We utilized phage-display technology to generate a novel anti-HER2 mAb (named 73JIgG) that binds an epitope of HER2 distinct from that of trastuzumab. Although these mAbs bind to the same cell surface receptor, they have different cell distribution profiles. After 3h of incubation, almost 10% of the total 73JIgG reaches the lysosome compared to less than 3% of trastuzumab. Interestingly, 73JIgG disassociates from HER2 whereas trastuzumab remains bound to the receptor. Importantly, HER2 distribution is not affected by the antibody binding epitope, thus negating this mechanism as the reason for the difference in intracellular trafficking of 73JIgG versus trastuzumab. Each of trastuzumab and 73JIgG was chemically-modified with either a small molecule or polymeric nanoparticle to better understand the influence of conjugation on cellular localization. Relative to antibody alone, antibody-nanoparticle conjugates resulted in a higher concentration of antibodies in the lysosome whereas antibody-small molecule conjugates did not affect cell trafficking to the lysosome. Given the importance of lysosomal targeting, these results demonstrate the importance of understanding the influence of the antibody-conjugate on cell trafficking for ultimate optimization of treatment selection.

Effect of normothermic cardiopulmonary bypass on renal injury in pediatric cardiac surgery: a randomized controlled trial.

OBJECTIVE: Hypothermic cardiopulmonary bypass (CPB), although associated with a reduction in oxygen requirement, has a number of disadvantages including detrimental effects on enzymatic function, energy generation, and cellular integrity. Normothermic perfusion is potentially a more physiologic method to maintain the functional integrity of major organ systems. One of the aims of this trial was to compare the effect of normothermic and hypothermic CPB on renal injury in pediatric patients undergoing cardiac surgery. METHODS: Fifty-nine children (median age, 78 months; interquartile range, 39-130) undergoing corrective cardiac surgery were randomized to either hypothermic (28°C) or normothermic (35°C-37°C) CPB. Urinary albumin, retinal binding protein (RBP) and N-acetyl-ß-glucosaminidase (NAG) were measured preoperatively, end of CPB, 4, and 24 hours postoperatively and were expressed as a ratio of urinary creatinine. Serum creatinine was measured preoperatively, end of CPB, and 24 and 48 hours postoperatively. Results are expressed as a difference in means (normotheric - hypothermic) or as a ratio of geometric means (normothermic/hypothermic). RESULTS: Baseline characteristics were similar in both groups. For these biochemical markers no significant interactions between treatment and postintervention time were found. Serum creatinine (-2.10; 95% confidence interval [CI], -6.51-2.31), RBP (ratio, 0.96; 95% CI, 0.65-1.41), and NAG (ratio, 0.86; 95% CI, 0.56-1.36) were similar in the 2 groups (P ≥ .34), but the urinary albumin was significantly lower in the normothermic group (ratio, 0.63; 95% CI, 0.42-0.95, P = .03). CONCLUSIONS: Normothermic CPB is associated with similar renal impairment to hypothermic CPB in children undergoing heart surgery.