Evaluating CD133 as a Radiotheranostic Target in Small-Cell Lung Cancer.

Despite decades of work, small-cell lung cancer (SCLC) remains a frustratingly recalcitrant disease. Both diagnosis and treatment are challenges: low-dose computed tomography (the approved method used for lung cancer screening) is unable to reliably detect early SCLC, and the malignancy's 5 year survival rate stands at a paltry 7%. Clearly, the development of novel diagnostic and therapeutic tools for SCLC is an urgent, unmet need. CD133 is a transmembrane protein that is expressed at low levels in normal tissue but is overexpressed by a variety of tumors, including SCLC. We previously explored CD133 as a biomarker for a novel autoantibody-to-immunopositron emission tomography (PET) strategy for the diagnosis of SCLC, work that first suggested the promise of the antigen as a radiotheranostic target in the disease. Herein, we report the in vivo validation of a pair of CD133-targeted radioimmunoconjugates for the PET imaging and radioimmunotherapy of SCLC. To this end, [89Zr]Zr-DFO-αCD133 was first interrogated in a trio of advanced murine models of SCLC─i.e., orthotopic, metastatic, and patient-derived xenografts─with the PET probe consistently producing high activity concentrations (>%ID/g) in tumor lesions combined with low uptake in healthy tissues. Subsequently, a variant of αCD133 labeled with the ß-emitting radiometal 177Lu─[177Lu]Lu-DTPA-A″-CHX-αCD133─was synthesized and evaluated in a longitudinal therapy study in a subcutaneous xenograft model of SCLC, ultimately revealing that treatment with a dose of 9.6 MBq of the radioimmunoconjugate produced a significant increase in median survival compared to a control cohort. Taken together, these data establish CD133 as a viable target for the nuclear imaging and radiopharmaceutical therapy of SCLC.

Leveraging a Dual Variable Domain Immunoglobulin to Create a Site-Specifically Modified Radioimmunoconjugate.

Site-specifically modified radioimmunoconjugates exhibit superior in vitro and in vivo behavior compared to analogues synthesized via traditional stochastic methods. However, the development of approaches to site-specific bioconjugation that combine high levels of selectivity, simple reaction conditions, and clinical translatability remains a challenge. Herein, we describe a novel solution to this problem: the use of dual-variable domain immunoglobulins (DVD-IgG). More specifically, we report the synthesis, in vitro evaluation, and in vivo validation of a 177Lu-labeled radioimmunoconjugate based on HER2DVD, a DVD-IgG containing the HER2-targeting variable domains of trastuzumab and the catalytic variable domains of IgG h38C2. To this end, we first modified HER2DVD with a phenyloxadiazolyl methlysulfone-modified variant of the chelator CHX-A″-DTPA (PODS-CHX-A''-DTPA) and verified the site-specificity of the conjugation for the reactive lysines within the catalytic domains via chemical assay, MALDI-ToF mass spectrometry, and SDS-PAGE. The chelator-bearing immunoconjugate was subsequently labeled with [177Lu]Lu3+ to produce the completed radioimmunoconjugate, [177Lu]Lu-CHX-A″-DTPAPODS-HER2DVD, in >80% radiochemical conversion and a specific activity of 29.5 ± 7.1 GBq/µmol. [177Lu]Lu-CHX-A″-DTPAPODS-HER2DVD did not form aggregates upon prolonged incubation in human serum, displayed 87% stability to demetalation over a 7 days of incubation in serum, and exhibited an immunoreactive fraction of 0.95 with HER2-coated beads. Finally, we compared the pharmacokinetic profile of [177Lu]Lu-CHX-A″-DTPAPODS-HER2DVD to that of a 177Lu-labeled variant of trastuzumab in mice bearing subcutaneous HER2-expressing BT-474 human breast cancer xenografts. The in vivo performance of [177Lu]Lu-CHX-A″-DTPAPODS-HER2DVD matched that of 177Lu-labeled trastuzumab, with the former producing a tumoral activity concentration of 34.1 ± 12.1 %ID/g at 168 h and tumor-to-blood, tumor-to-liver, and tumor-to-kidney activity concentration ratios of 10.5, 9.6, and 21.8, respectively, at the same time point. Importantly, the DVD-IgG did not exhibit a substantially longer serum half-life than the traditional IgG despite its significantly larger size (202 kDa for the former vs 148 kDa for the latter). Taken together, these data suggest that DVD-IgGs represent a viable platform for the future development of highly effective site-specifically labeled radioimmunoconjugates for diagnostic imaging, theranostic imaging, and radioimmunotherapy.

Visualizing Galectin-3 Binding Protein Expression with ImmunoPET.

Galectin-3 binding protein (Gal-3BP) is a glycoprotein that is overexpressed and secreted by several cancers and has been implicated as a marker of both tumor progression and poor prognosis in melanoma, non-small cell lung cancer, head and neck squamous cell carcinoma, and breast cancer. The expression of Gal-3BP by a variety of neoplasms makes it an enticing target for both diagnostics and therapeutics, including immuno-positron emission tomography (immunoPET) probes and antibody-drug conjugates (ADCs). Herein, we report the development, in vitro characterization, and in vivo evaluation of a pair of Gal-3BP-targeting radioimmunoconjugates for 89Zr-immunoPET. A humanized anti-Gal-3BP antibody, 1959, and its corresponding ADC, 1959-sss/DM4 (DM4 = ravtansine), were modified with desferrioxamine (DFO) to yield DFO-1959 and DFO-1959-sss/DM4 immunoconjugates bearing 1-2 DFO/monoclonal antibody. Both DFO-modified immunoconjugates retained their affinity for Gal-3BP in enzyme-linked immunosorbent assay experiments. The chelator-bearing antibodies were radiolabeled with zirconium-89 (t1/2 ≈ 3.3 d) to produce radioimmunoconjugates ─ [89Zr]Zr-DFO-1959 and [89Zr]Zr-DFO-1959-sss/DM4 ─ with high specific activity (>444 MBq/mg, >12 mCi/mg) and stability (>80% intact after 168 h in human serum at 37 °C). In mice bearing subcutaneous Gal-3BP-secreting A375-MA1 xenografts, [89Zr]Zr-DFO-1959 clearly delineated tumor tissue, reaching a maximum tumoral activity concentration (54.8 ± 15.8%ID/g) and tumor-to-background contrast (tumor-to-blood = 8.0 ± 4.6) at 120 h post-injection. The administration of [89Zr]Zr-DFO-1959 to mice bearing subcutaneous Gal-3BP-expressing melanoma patient-derived xenografts produced similarly promising results. [89Zr]Zr-DFO-1959 and [89Zr]Zr-DFO-1959-sss/DM4 exhibited nearly identical pharmacokinetic profiles in the mice bearing A375-MA1 tumors, though the latter produced higher uptake in the spleen and kidneys. Both [89Zr]Zr-DFO-1959 and [89Zr]Zr-DFO-1959-sss/DM4 effectively visualized Gal-3BP-secreting tumors in murine models of melanoma. These results suggest that both probes could play a role in the clinical imaging of Gal-3BP-expressing malignancies, particularly as companion theranostics for the identification of patients likely to respond to Gal-3BP-targeted therapeutics such as 1959-sss/DM4.

Lysine-Directed Site-Selective Bioconjugation for the Creation of Radioimmunoconjugates.

The synthesis of radioimmunoconjugates via the stochastic attachment of bifunctional chelators to lysines can yield heterogeneous products with suboptimal in vitro and in vivo behavior. In response to this, several site-selective approaches to bioconjugation have been developed, yet each has intrinsic drawbacks, such as the need for expensive reagents or the complexity of incorporating unnatural amino acids into IgGs. Herein, we describe the use of a simple and facile approach to lysine-directed site-selective bioconjugation for the generation of radioimmunoconjugates. This strategy relies upon on the selective modification of single lysine residues within each light chain of the monoclonal antibody (mAb) with a branched azide-bearing perfluorophenyl ester (PFP-bisN3) followed by the ligation of dibenzocyclooctyne (DBCO)-bearing payloads to these bioorthogonal handles via the strain-promoted azide-alkyne cycloaddition. This methodology was used to create [89Zr]Zr-SSKDFO-pertuzumab, a radioimmunoconjugate of the HER2-targeting mAb pertuzumab labeled with desferrioxamine (DFO) and the positron-emitting radiometal zirconium-89 (89Zr). [89Zr]Zr-SSKDFO-pertuzumab was compared to a pair of analogous probes: one synthesized via random lysine modification ([89Zr]Zr-DFO-pertuzumab) and another via thiol-maleimide chemistry ([89Zr]Zr-malDFO-pertuzumab). The bioconjugation strategy was assessed using ESI mass spectrometry, SDS-PAGE, and autoradiography. All three immunoconjugates demonstrated comparable binding to HER2 via flow cytometry and surface plasmon resonance (SPR), and 89Zr-labeled variants of each were synthesized in >99% radiochemical yield and molar activities of up to ∼55.5 GBq/µmol (10 mCi/mg). Subsequently, the in vivo behavior of this trio of 89Zr-immunoPET probes was interrogated in athymic nude mice bearing subcutaneous HER2-expressing BT-474 human breast cancer xenografts. [89Zr]Zr-SSKDFO-pertuzumab, [89Zr]Zr-malDFO-pertuzumab, and [89Zr]Zr-DFO-pertuzumab produced positron emission tomography (PET) images with high tumoral uptake and high tumor-to-healthy organ activity concentration ratios. A terminal biodistribution study complemented the PET results, revealing tumoral activity concentrations of 126.9 ± 50.3%ID/g, 86.9 ± 53.2%ID/g, and 92.5 ± 27.2%ID/g at 144 h post-injection for [89Zr]Zr-SSKDFO-pertuzumab, [89Zr]Zr-malDFO-pertuzumab, and [89Zr]Zr-DFO-pertuzumab, respectively. Taken together, the data clearly illustrate that this highly modular and facile approach to site-selective bioconjugation produces radioimmunoconjugates that are better-defined and more homogeneous than stochastically modified constructs and also exhibit excellent in vitro and in vivo performance. Furthermore, we contend that this lysine-directed strategy holds several key advantages over extant approaches to site-selective bioconjugation, especially in the context of production for the clinic.

Ovarian Preservation and Recurrent Torsion in Children: Both Less Common Than We Thought.

PURPOSE: Surgical management of pediatric ovarian torsion includes total oophorectomy (TO) or ovarian preservation surgery (OPS). This study sought to identify factors contributing to surgical management and readmission outcomes for ovarian torsion. METHODS: The Nationwide Readmission Database from 2010-2014 was used to identify patients < 18 years admitted with ovarian torsion. Patient factors, hospital characteristics, and readmission outcomes were compared by TO and OPS. Standard statistical analysis was performed and results were weighted for national estimates. RESULTS: There were 6028 patients (age 13 ± 4 years) identified with ovarian torsion who underwent either TO (50%) or OPS (50%). Patients had secondary pathology of ovarian cyst (41%), benign mass (19%), and malignant mass (0.4%). OPS was more common in teaching hospitals (84% vs. 74% TO, P<0.001), patients < 13 years of age (41% vs. 37% TO, P = 0.001), and those from high-income households (51% vs. 41% TO, P<0.001). The overall readmission rate was 4%, with no difference between surgical approach (4.3% OPS vs. 4.4% TO, P = 0.882). Of those readmitted (n = 265), readmission diagnoses were cyst (10%), malignant mass (9%), benign mass (7%), and torsion (5%). The overall rate of recurrent torsion was 0.2%, with no difference between OPS and TO (< 0.3% vs. < 0.2%, P = 0.282). CONCLUSION: Half of pediatric patients are undergoing TO for ovarian torsion in the U.S. and disparities exist with the utilization of OPS. There is no difference in rate of readmission or recurrent torsion between surgical approaches, and the overall rate of retorsion is lower than previously reported.

Predicting the outcome of initial non-surgical endodontic procedures by periapical status and quality of root canal filling: a cohort study.

To assess the previous periapical status and the quality of root canal filling as predictors of the outcome in initial non-surgical endodontic procedures. A retrospective cohort study was designed in which the presence of a previous periapical lesion was determined radiographically. The quality of the root filling was evaluated in terms of homogeneity, taper, and apical extension. The response variable was dichotomized to success and failure. Bivariate analyzes and a mixed generalized linear model interpreted the association between the explanatory variables and the outcome of the initial non-surgical endodontic procedures. A total of 349 roots were evaluated, and a failure rate of 13.18% was established. Poor filling quality was determined in 8.3% of the roots. As a main result, the presence of a preoperative periapical lesion did not determine a significant risk to the failure of the initial treatment. Unlike, a poor quality of the obturation determined association with an unfavorable outcome like this: (1) homogeneity (OR 2.32; p = 0.0181); (2) taper (OR 5.8; p = 0.0); and, (3) extension (OR 3.41; p = 0.0). Therefore, a significant association between inadequate quality of the root filling and failure of the primary non-surgical endodontic procedures was found. Short length of filling was highly associated with failure. The presence of previous periapical lesion was not found to be a significant predictor for treatment outcomes.

Evidence for maize (Zea mays) in the Late Archaic (3000-1800 B.C.) in the Norte Chico region of Peru.

For more than 40 y, there has been an active discussion over the presence and economic importance of maize (Zea mays) during the Late Archaic period (3000-1800 B.C.) in ancient Peru. The evidence for Late Archaic maize has been limited, leading to the interpretation that it was present but used primarily for ceremonial purposes. Archaeological testing at a number of sites in the Norte Chico region of the north central coast provides a broad range of empirical data on the production, processing, and consumption of maize. New data drawn from coprolites, pollen records, and stone tool residues, combined with 126 radiocarbon dates, demonstrate that maize was widely grown, intensively processed, and constituted a primary component of the diet throughout the period from 3000 to 1800 B.C.

Successful Retention Strategies for Research Targeting Hispanic/Latinx (Including Recent Immigrants) in the Midwest Region of the United States.

Recruiting and retaining Hispanic/Latinx (H/L) participants, specifically undocumented immigrants, is challenging in part because of the mistrust and fear in participating in research studies. Additionally, only a few longitudinal studies describe the recruit and retention strategies among Mexican and Central American immigrants aiming to expand the knowledge base about those underprivileged groups; this was the objective of the 6-year longitudinal VidaSana study. In the present methods report, we specifically omit the presentation of results from the empirical data findings of the VidaSana study: the present report describes the process and offers a subjective appraisal of multiple and complementary approaches in the recruitment and retention strategies for Hispanics living in the Midwest region of the United States, including very recently arrived immigrants. This study was able to effectively recruit and retain (81.7%) a cohort of Mexican and Central American immigrants within a period of 36 months. Our recruitment and retention performance were successful in the context of the hostile environment against immigration that dominated the national landscape at the time of our study. The present methods report of the VidaSana study provides an insightful understanding in recruiting and, in particular, retaining H/Ls and H/L recent immigrants into longitudinal studies.

Molecular Imaging in Gynecology: Beyond Cancer.

Gynecological pathologies account for approximately 4.5% of the overall global disease burden. Although cancers of the female reproductive system have understandably been the focus of a great deal of research, benign gynecological conditions-such as endometriosis, polycystic ovary syndrome, and uterine fibroids-have remained stubbornly understudied despite their astonishing ubiquity and grave morbidity. This historical inattention has frequently become manifested in flawed diagnostic and treatment paradigms. Molecular imaging could be instrumental in improving patient care on both fronts. In this Focus on Molecular Imaging review, we will examine recent advances in the use of PET, SPECT, MRI, and fluorescence imaging for the diagnosis and management of benign gynecological conditions, with particular emphasis on recent clinical reports, areas of need, and opportunities for growth.

Contemporary Trends in Laparoscopy and Ovarian Sparing Surgery for Ovarian Torsion in the Pediatric Population.

PURPOSE: Although total oophorectomy (TO) was historically performed in cases of nonviable-appearing ovaries, considerable evidence has demonstrated equivalent outcomes after ovarian sparing surgery (OSS) as well as long-term fertility preservation benefits. This study sought to compare outcomes of OSS and TO for patients with ovarian torsion. METHODS: Females <21 years old admitted for ovarian torsion were identified from the Nationwide Readmissions Database (2016-2018) and stratified by OSS or TO. Propensity score-matched analysis (PSMA) utilizing >50 covariates (demographics, medical comorbidities, ovarian diagnoses, etc.) was constructed between those receiving TO and OSS. RESULTS: There were 3,161 females (median 15 [12-18] years) with ovarian torsion, and concomitant pathologies included cysts (42%), benign masses (25%), and malignant masses (<1%). Open approaches were more common (52% vs. 48% laparoscopic), and ovarian resection (OSS or TO) was performed in 87% (39% OSS and 48% TO). OSS was more commonly performed with laparoscopic detorsions (60% vs. 40% TO), while TO was more frequent in open operations (59% vs. 41% TO; both p < 0.001). No differences in overall readmissions (7% OSS vs. 8% TO) or readmissions for recurrent torsion (<1% overall) and ovarian masses (<1%) were observed (both groups <1%; p = 0.612). After PSMA, laparoscopy was still utilized less frequently with TO (39% vs. 53%; p < 0.001) despite similar rates of malignant masses. CONCLUSIONS: Overall, these data offer additional support for the current practice guidelines that give preference to OSS as the primary method of treatment for pediatric ovarian torsion in the majority of cases. LEVEL OF EVIDENCE: III. TYPE OF STUDY: Retrospective Comparative Study.

Uncovering Risk Factors and Outcomes of Pulmonary Embolism in a Nationwide Cohort of Hospitalized Children.

PURPOSE: The incidence of pulmonary embolism (PE) in hospitalized children has increased in recent years. This study sought to characterize factors and outcomes associated with PE using a national pediatric cohort. METHODS: The Nationwide Readmissions Database was queried (2016-2018) for patients (<18 years) with a diagnosis of PE. Index and prior hospitalizations (PHs) within 1 year were analyzed. A binary logistic regression utilizing 37 covariates (demographics, procedures, comorbidities, etc.) was constructed to examine a primary outcome of in-hospital mortality. RESULTS: 3440 patients were identified (57% female) with the majority >12 years old (77%). One-third had a known deep vein thrombosis (69% lower and 31% upper extremity). Nineteen percent underwent central venous catheter (CVC) placement. Twenty-one percent had a PH within 1 year. Nine percent underwent an operation with the majority being cardiothoracic (5%). Overall mortality was 5%. Neurocranial surgery, cardiothoracic surgery, and CVC placement were associated with the highest odds of inpatient mortality after logistic regression. CONCLUSION: Pediatric patients with PE have a high rate of PHs, CVC placement, and inpatient operations, which may be associated with higher mortality. This information can be utilized to improve screening measures and clinical suspicion for PE in hospitalized children.

Assessment of the national school lunch program in a subset of schools in San Juan, Puerto Rico: participants vs. non-participants.

OBJECTIVE: Extensive evaluations of the national school lunch program (NSLP) have been carried out on the U.S. mainland. Puerto Rico, a commonwealth of the U.S. is a participant in this program, but has never been included in assessment studies. Herein, we present assessment information and compare results with comparable mainland studies. METHODS: Multiple 24-hr recall questionnaires were administered to groups of participating (P) and non-participating (NP) children in the lunch program at 3 educational levels. Comparisons were made for children within the study as well as between comparable children in mainland studies for total intake of several macro- and micro-nutrients, contribution of the lunch to the total daily intake and adherence to U.S. Recommended Dietary Allowances (RDA's) or to Dietary Reference Intakes (DRI's) including acceptable macronutrient distribution ranges (AMDR's). RESULTS: Target intakes were met by P for % of the RDA of energy from protein, for all water soluble vitamins, iron, zinc and cholesterol. P did not achieve target intakes for total energy, energy from carbohydrates and fat nor for fat soluble vitamins, calcium, magnesium, phosphorus, potassium and fiber. Recommended levels were exceeded for sodium, total fat and saturated fat. Comparing P vs NP, the vast majority of both groups fell within AMDR recommendations for macronutrients but not all micronutrients. CONCLUSION: For the most part, our results parallel those obtained in the National sample however, results suggest that P in the lunch program in Puerto Rico have a healthier intake of several nutrients than NP students. The unique feature of this study is that it is the first assessment of the NSLP in a completely Hispanic population.

High Carbohydrate vs High Fat Diets: Which is Preferable for Long-term Use?

Background: Commercial manufacturers have formulated diets to promote not only weight reduction but also to reduce risks of chronic diseases. Objective: To determine if these formulations satisfy requirements for essential nutrients and their suitability for long term use. Methods: We have selected two established commercial diets, one high carbohydrate, low fat (diet 1) and the other, low carbohydrate, high fat (diet 2) and determined "representative meals" through use of recipes suggested in the manufacturer's manuals. Nutrition Data System for Research (NDSR) software has been used to perform the most extensive nutrient analysis to date of these diets. Results: Tables report macronutrients (energy), vitamins, minerals, essential amino acids, essential fatty acids and nutrient-related components for a total of 62 entries. Diet 1 satisfied requirements for 50 of these (81%) with only vitamin B12, vitamin D, and essential fatty acids not reaching recommended levels, while fiber and glycemic load exceeded suggested values. Diet 2 satisfied requirements for forty- six of the components (71%) but had excess percentage of fat, especially saturated fat, sodium and cholesterol as well as decreased percentage of carbohydrate resulting in suboptimal intake of B-complex vitamins (B1, niacin and total folate) as well as fiber. Conclusions: Neither diet satisfied adequacies for all reported nutrients. However, based on nutrient content alone diet 1, if supplemented, could be sustained over the long term whereas diet 2, even if supplemented, should not be encouraged for long term adaptation.

Unraveling the in vivo fate of inhaled micro- and nanoplastics with PET imaging.

Microplastics and nanoplastics have become ubiquitous environmental pollutants. The threat these plastics pose to human health has fueled research focused on their pathophysiology and toxicology, yet many of their fundamental properties - for example, their in vivo pharmacokinetics - remain poorly understood. In this investigation, we have harnessed positron emission tomography (PET) to track the in vivo fate of micro- and nanoplastics administered to mice intratracheally and intravenously. To this end, 1 µm and 20 nm diameter amine-functionalized polystyrene particles were modified with an isothiocyanate-bearing variant of desferrioxamine (DFO) and radiolabeled with the positron-emitting radiometal [89Zr]Zr4+. Both radioplastics - [89Zr]Zr-DFO-PS1000 and [89Zr]Zr-DFO-PS20 - were produced in ∼95% radiochemical yield and found to be >85% stable to demetallation over one week at 37 °C in human serum and simulated lung fluid. The incubation of [89Zr]Zr-DFO-PS1000 and [89Zr]Zr-DFO-PS20 with MH-S cells revealed that the majority of the former were phagocytosed by alveolar macrophages within 4 h, while the latter largely evaded consumption. Finally, the in vivo behavior of the radioplastics was interrogated in mice upon intravenous and intratracheal administration. PET imaging and biodistribution experiments revealed that the intravenously injected plastics accumulated primarily in the liver and spleen, yielding hepatic radioactivity concentrations of 101 ± 48 %ID/g and 92 ± 22 %ID/g at 168 h post-injection for [89Zr]Zr-DFO-PS1000 and [89Zr]Zr-DFO-PS20, respectively. In contrast, the mice that received the radioplastics via intratracheal installation displayed the highest uptake in the lungs at the end of one week: 4 ± 2 %ID/g for [89Zr]Zr-DFO-PS1000 and 32 ± 6 %ID/g for [89Zr]Zr-DFO-PS20. Ultimately, this work illustrates the critical role that the route of exposure plays in the bioaccumulation of plastic particles, reveals that size dramatically influences the pulmonary retention of inhaled particles, and underscores the value of PET imaging as a tool for studying the pharmacokinetics of environmental pollutants.

Site-selective radiolabeling using mushroom tyrosinase and the strain-promoted oxidation-controlled 1,2-quinone cycloaddition.

We report the in vitro characterization and in vivo evaluation of a novel 89Zr-labeled radioimmunoconjugate synthesized using a site-selective bioconjugation strategy based on the oxidation of tyrosinase residues exposed by the deglycosylation of the IgG and the subsequent strain-promoted oxidation-controlled 1,2-quinone cycloaddition between these amino acids and trans-cyclooctene-bearing cargoes. More specifically, we site-selectively modified a variant of the A33 antigen-targeting antibody huA33 with the chelator desferrioxamine (DFO), thereby producing an immunoconjugate (DFO-SPOCQhuA33) with equivalent antigen binding affinity to its parent immunoglobulin but attenuated affinity for the FcγRI receptor. This construct was subsequently radiolabeled with [89Zr]Zr4+ to create a radioimmunoconjugate - [89Zr]Zr-DFO-SPOCQhuA33 - in high yield and specific activity that exhibited excellent in vivo behavior in two murine models of human colorectal carcinoma.

Income Disparities in Nationwide Outcomes of Malrotation with Midgut Volvulus.

BACKGROUND: Malrotation with midgut volvulus is a surgical emergency commonly encountered in pediatric surgical practice. Outcomes are excellent with timely diagnosis and treatment, but the development of bowel ischemia is associated with many negative consequences. METHODS: The Nationwide Readmissions Database was used to identify patients 0-18 years (excluding newborns) with malrotation and midgut volvulus from 2010 to 2014. Demographics, procedures, and outcomes were compared by income group (highest quartile vs. lowest quartile) using standard statistical tests. Results were weighted for national estimates. RESULTS: Emergency surgery for midgut volvulus was performed in 572 patients. The majority (86%) underwent Ladd's procedure, while 14% required bowel resection and/or ostomy. Patients in the lowest income quartile were more likely to require bowel resection (18% vs. 8%, p = 0.03) or ostomy (9% vs. 2%, p = 0.015) compared to those in the highest income quartile. Low-income patients were more likely to experience prolonged hospital stay (8 [5-13] days vs. 6 [4-8] days, p<0.001) and experience complications including infections (19% vs. 5%, p = 0.002), endotracheal intubation (18% vs. 4%, p<0.001), and blood transfusions (13% vs. 3%, p = 0.003). CONCLUSION: Income disparity represents a major factor in surgical outcomes in children with midgut volvulus. A broad spectrum of clinical outcomes following surgery for midgut volvulus exists. Patients from lower-income communities are at significantly higher risk for numerous complications, negative outcomes, and higher resource utilization. These findings support additional investigations of practices to mitigate risk for low-income patients. LEVEL OF EVIDENCE: Level III: Retrospective comparative study.

Nationwide Outcomes of Pancreaticoduodenectomy for Pancreatic Malignancies: Center Volume Matters.

BACKGROUND: Complex surgeries such as pancreaticoduodenectomies (PD) have been shown to have better outcomes when performed at high-volume centers (HVCs) compared to low-volume centers (LVCs). Few studies have compared these factors on a national level. The purpose of this study was to analyze nationwide outcomes for patients undergoing PD across hospital centers with different surgical volumes. METHODS: The Nationwide Readmissions Database (2010-2014) was queried for all patients who underwent open PD for pancreatic carcinoma. High-volume centers were defined as hospitals where 20 or more PDs were performed per year. Sociodemographic factors, readmission rates, and perioperative outcomes were compared before and after propensity score-matched analysis (PSMA) for 76 covariates including demographics, hospital factors, comorbidities, and additional diagnoses. Results were weighted for national estimates. RESULTS: A total of 19,810 patients were identified with age 66 ± 11 years. There were 6,840 (35%) cases performed at LVCs, and 12,970 (65%) at HVCs. Patient comorbidities were greater in the LVC cohort, and more PDs were performed at teaching hospitals in the HVC cohort. These discrepancies were controlled for with PSMA. Length of stay (LOS), mortality, invasive procedures, and perioperative complications were greater in LVCs when compared to HVCs before and after PSMA. Additionally, readmission rates at one year (38% vs 34%, P < .001) and readmission complications were greater in the LVC cohort. CONCLUSIONS: Pancreaticoduodenectomy is more commonly performed at HVCs, which is associated with less complications and improved outcomes compared to LVCs.

Stress and Alcohol Intake among Hispanic Adult Immigrants in the U.S. Midwest.

Alcohol intake and Alcohol Use Disorder (AUD) among recent and very recent Hispanic immigrants are not well characterized, in particular in the context of perceived stress among such groups. The objective of the present study was to shed light on alcohol intake and AUD overall, as well as potential modifications derived from varying levels of stress and socioeconomic status (SES). The study population was immigrants with six or fewer months of having arrived in the American Midwest, and members of their peer networks who had been in the U.S. for 2+ years. We found that AUD and alcohol intake spanned from very high to a considerable proportion who abstained; perceived stress did not have an obvious impact on AUD or alcohol intake. Moreover, neither New vs. Established immigrant statuses, or SES levels, were associated with AUD or alcohol intake. Future research should examine in a more finely-grained approach the components of SES to verify if the complex circumstances of recent immigrants are in fact amenable to SES classification using standard quantification approaches-even using the functional descriptions of the SES surrogates we used.

Antibody Engineering for Nuclear Imaging and Radioimmunotherapy.

Radiolabeled antibodies have become indispensable tools in nuclear medicine. However, the natural roles of antibodies within the immune system mean that they have several intrinsic limitations as a platform for radiopharmaceuticals. In recent years, the field has increasingly turned to antibody engineering to circumvent these issues while retaining the manifold benefits of the immunoglobulin framework. In this "Focus on Molecular Imaging" review, we cover recent advances in the application of antibody engineering to immunoPET, immunoSPECT, and radioimmunotherapy. Specifically, we address how antibody engineering has been used to improve radioimmunoconjugates on four fronts: optimizing pharmacokinetics, facilitating site-specific bioconjugation, modulating Fc interactions, and creating bispecific constructs.

CD133 as a Biomarker for an Autoantibody-to-ImmunoPET Paradigm for the Early Detection of Small Cell Lung Cancer.

Small cell lung cancer (SCLC) is a deadly neuroendocrine tumor for which there are no screening methods sensitive enough to facilitate early, effective intervention. We propose targeting the neuroendocrine tumor neoantigen CD133 via antibody-based early detection and PET (immunoPET) to facilitate earlier and more accurate detection of SCLC. Methods: RNA sequencing datasets, immunohistochemistry, flow cytometry, and Western blots were used to quantify CD133 expression in healthy and SCLC patients. CD133 was imaged in vivo using near-infrared fluorescence (NIRF) immunoimaging, and 89Zr immunoPET. Anti(α)-CD133 autoantibody levels were measured in SCLC patient plasma using antibody microarrays. Results: Across 6 publicly available datasets, CD133 messenger RNA was found to be higher in SCLC tumors than in other tissues, including healthy or normal adjacent lung and non-SCLC samples. Critically, the upregulation of CD133 messenger RNA in SCLC was associated with a significant increase (hazard ratio, 2.62) in death. CD133 protein was expressed in primary human SCLC, in SCLC patient-derived xenografts, and in both SCLC cell lines tested (H82 and H69). Using an H82 xenograft mouse model, we first imaged CD133 expression with NIRF. Both in vivo and ex vivo NIRF clearly showed that a fluorophore-tagged αCD133 homed to lung tumors. Next, we validated the noninvasive visualization of subcutaneous and orthotopic H82 xenografts via immunoPET. An αCD133 antibody labeled with the positron-emitting radiometal 89Zr demonstrated significant accumulation in tumor tissue while producing minimal uptake in healthy organs. Finally, plasma αCD133 autoantibodies were found in subjects from cohort studies up to 1 year before SCLC diagnosis. Conclusion: In light of these findings, we conclude that the presence of αCD133 autoantibodies in a blood sample followed by CD133-targeted 89Zr-immunoPET could be an effective early detection screening strategy for SCLC.