Relative biological effectiveness of clinically relevant photon energies for the survival of human colorectal, cervical, and prostate cancer cell lines.

Objective:Relative biological effectiveness (RBE) differs between radiation qualities. However, an RBE of 1.0 has been established for photons regardless of the wide range of photon energies used clinically, the lack of reproducibility in radiobiological studies, and outdated reference energies used in the experimental literature. Moreover, due to intrinsic radiosensitivity, different cancer types have different responses to radiation. This study aimed to characterize the RBE of clinically relevant high and low photon energiesin vitrofor three human cancer cell lines: HCT116 (colon), HeLa (cervix), and PC3 (prostate).Approach:Experiments were conducted following dosimetry protocols provided by the American Association of Physicists in Medicine. Cells were irradiated with 6 MV x-rays, an192Ir brachytherapy source, 225 kVp and 50 kVp x-rays. Cell survival post-irradiation was assessed using the clonogenic assay. Survival fractions were fitted using the linear quadratic model, and the survival curves were generated for RBE calculations.Main results:The cell killing was more efficient with decreasing photon energy: the HCT116 RBESF0.1for 6 MV x-rays,192Ir, and 50 kVp x-rays using 225 kVp x-rays as the reference were 0.89 ± 0.03, 0.95 ± 0.03, and 1.24 ± 0.04; the HeLa RBESF0.1were 0.95 ± 0.04, 0.97 ± 0.05, and 1.09 ± 0.03, and the PC3 RBESF0.1were 0.84 ± 0.01, 0.84 ± 0.01, and 1.13 ± 0.02, respectively. HeLa and PC3 cells had varying radiosensitivity when irradiated with 225 and 50 kVp x-rays.Significance:This difference supports the notion that RBE may not be 1.0 for all photons through experimental investigations that employed precise dosimetry. It highlights that different cancer types may not have identical responses to the same irradiation quality. Additionally, the RBE of clinically relevant photons was updated to the reference energy of 225 kVp x-rays.

Use of low titer O whole blood in infants and young children undergoing cardiac surgery with cardiopulmonary bypass.

BACKGROUND: Low titer group O whole blood (LTOWB) is commonly used for severe bleeding in trauma patients. LTOWB may also benefit young children requiring cardiac surgery with cardiopulmonary bypass (CPB) at risk of severe bleeding. STUDY DESIGN AND METHODS: In this retrospective study, children <2 years old who underwent cardiac surgery with CPB were included. Comparisons were performed between those receiving component therapy (CT) versus those receiving LTOWB plus CT (LTOWB+CT). Outcomes included drainage tube (DT) output and total transfusion volumes. Optimization-based weighting was used for adjusted analyses between groups. RESULTS: There were 117 patients transfused with only CT and 127 patients transfused with LTOWB+CT. In the LTOWB+CT group, 66 were Group non-O and 61 were Group O. Total transfusion volumes given from the start of the operation until the first 24 h in the cardiac intensive care unit was a median (IQR) 41 (10, 93) mL/kg in the CT group and 48 (28, 77) mL/kg in the LTOWB+CT group, (p = .28). Median (IQR) DT output was 22 (15-32) in CT versus 22 (16-28) in LTOWB+CT groups, (p = .27). There were no differences in death, renal failure and a composite of death and renal failure between the two groups, but there were statistically fewer re-explorations for bleeding in the LTOWB+CT group (p < .001). CONCLUSIONS: The use of LTOWB appears to be safe in <2 years old undergoing cardiac surgery and may reduce re-explorations for severe bleeding. Large trials are needed to determine the efficacy and safety of LTOWB in this population with severe bleeding.

A lactobacilli-based inhaled live biotherapeutic product attenuates pulmonary neutrophilic inflammation.

Bronchopulmonary dysplasia (BPD) is a chronic lung disease of prematurity. Exposure to noxious stimuli such as hyperoxia, volutrauma, and infection in infancy can have long-reaching impacts on lung health and predispose towards the development of conditions such as chronic obstructive pulmonary disease (COPD) in adulthood. BPD and COPD are both marked by lung tissue degradation, neutrophil influx, and decreased lung function. Both diseases also express a change in microbial signature characterized by firmicute depletion. However, the relationship between pulmonary bacteria and the mechanisms of downstream disease development has yet to be elucidated. We hypothesized that murine models of BPD would show heightened acetylated proline-glycine-proline (Ac-PGP) pathway and neutrophil activity, and through gain- and loss-of-function studies we show that Ac-PGP plays a critical role in driving BPD development. We further test a inhaled live biotherapeutic (LBP) using active Lactobacillus strains in in vitro and in vivo models of BPD and COPD. The Lactobacillus-based LBP is effective in improving lung structure and function, mitigating neutrophil influx, and reducing a broad swath of pro-inflammatory markers in these models of chronic pulmonary disease via the MMP-9/PGP (matrix metalloproteinase/proline-glycine-proline) pathway. Inhaled LBPs show promise in addressing common pathways of disease progression that in the future can be targeted in a variety of chronic lung diseases.

School Connectedness and Adolescent E-cigarette Susceptibility in an Urban Sample of Middle and High School Students.

Adolescent school connectedness generally protects from risk behaviors such as tobacco use; however, its relationship to e-cigarette use is unclear. This study examines the relationship between adolescent school connectedness and e-cigarette susceptibility in a diverse longitudinal sample. This secondary analysis of a school-based intervention surveyed 608 middle (66%) and high school (34%) students from 10 schools at 3 time points over 1 year. At baseline, respondents had a mean age of 14 years, 54% were female, and 71% were BIPOC (Black, Indigenous, People of Color). Logistic regression models examined unadjusted and adjusted associations between school connectedness (both baseline and concurrent) and e-cigarette susceptibility over time. E-cigarettes represented the most prevalent form of current nicotine-containing product use in spring 2019 (2.3%), and most respondents reported no e-cigarette susceptibility (69%). E-cigarette susceptibility remained relatively stable during the study. Higher baseline school connectedness levels were associated with lower odds of e-cigarette susceptibility over time. Similarly, higher concurrent school connectedness scores were associated with lower odds of e-cigarette susceptibility over time: spring 2019 (OR, 0.39; 95% CI, 0.32, 0.47), fall 2019 (OR, 0.49; 95% CI, 0.34, 0.72), and spring 2020 (OR, 0.64; 95% CI, 0.47, 0.87). Findings were similar for middle and high school students and did not differ significantly after adjusting for other covariates. Adolescents' school connectedness appears to protect from e-cigarette susceptibility over time, underscoring the importance of promoting positive school experiences to reduce adolescent risk e-cigarette use.

Low cost, high temporal resolution optical fiber-based γ-photon sensor for real-time pre-clinical evaluation of cancer-targeting radiopharmaceuticals.

Cancer radiopharmaceutical therapies (RPTs) have demonstrated great promise in the treatment of neuroendocrine and prostate cancer, giving hope to late-stage metastatic cancer patients with currently very few treatment options. These therapies have sparked a large amount of interest in pre-clinical research due to their ability to target metastatic disease, with many research efforts focused towards developing and evaluating targeted RPTs for different cancer types in in vivo models. Here we describe a method for monitoring real-time in vivo binding kinetics for the pre-clinical evaluation of cancer RPTs. Recognizing the significant heterogeneity in biodistribution of RPTs among even genetically identical animal models, this approach offers long-term monitoring of the same in vivo organism without euthanasia in contrast to ex vivo tissue dosimetry, while providing high temporal resolution with a low-cost, easily assembled platform, that is not present in small-animal SPECT/CTs. The method utilizes the developed optical fiber-based γ-photon biosensor, characterized to have a wide linear dynamic range with Lutetium-177 (177Lu) activity (0.5-500 µCi/mL), a common radioisotope used in cancer RPT. The probe's ability to track in vivo uptake relative to SPECT/CT and ex vivo dosimetry techniques was verified by administering 177Lu-PSMA-617 to mouse models bearing human prostate cancer tumors (PC3-PIP, PC3-flu). With this method for monitoring RPT uptake, it is possible to evaluate changes in tissue uptake at temporal resolutions <1 min to determine RPT biodistribution in pre-clinical models and better understand dose relationships with tumor ablation, toxicity, and recurrence when attempting to move therapies towards clinical trial validation.

SENTRI: Single-Particle Energy Transducer for Radionuclide Injections for Personalized Targeted Radionuclide Cancer Therapy.

PURPOSE: Targeted radionuclide therapy (TRT), whereby a tumor-targeted molecule is linked to a therapeutic beta- or alpha-emitting radioactive nuclide, is a promising treatment modality for patients with metastatic cancer, delivering radiation systemically. However, patients still progress due to suboptimal dosing, driven by the large patient-to-patient variability. Therefore, the ability to continuously monitor the real-time dose deposition in tumors and organs at risk provides an additional dimension of information during clinical trials that can enable insights into better strategies to personalize TRT. METHODS AND MATERIALS: Here, we present a single beta-particle sensitive dosimeter consisting of a 0.27-mm3 monolithic silicon chiplet directly implanted into the tumor. To maximize the sensitivity and have enough detection area, minimum-size diodes (1 µm2) are arrayed in 64 × 64. Signal amplifiers, buffers, and on-chip memories are all integrated in the chip. For verification, PC3-PIP (prostate-specific membrane antigen [PSMA]+) and PC3-flu (PSMA-) cell lines are injected into the left and right flanks of the mice, respectively. The devices are inserted into each tumor and measure activities at 5 different time points (0-2 hours, 7-9 hours, 12-14 hours, 24-26 hours, and 48-50 hours) after 177Lu-PSMA-617 injections. Single-photon emission computed tomography/computed tomography scans are used to verify measured data. RESULTS: With a wide detection range from 0.013 to 8.95 MBq/mL, the system is capable of detecting high tumor uptake as well as low doses delivered to organs at risk in real time. The measurement data are highly proportional (R2 > 0.99) to the 177Lu-PSMA-617 activity. The in vivo measurement data agree well with the single-photon emission computed tomography/computed tomography results within acceptable errors (±1.5%ID/mL). CONCLUSIONS: Given the recent advances in clinical use of TRT in prostate cancer, the proposed system is verified in a prostate cancer mouse model using 177Lu-PSMA-617.

Single-dose 177Lu-PSMA-617 followed by maintenance pembrolizumab in patients with metastatic castration-resistant prostate cancer: an open-label, dose-expansion, phase 1 trial.

BACKGROUND: Checkpoint inhibitors have been shown to have limited activity in patients with metastatic castration-resistant prostate cancer. We aimed to determine whether a single dose of lutetium-177 [177Lu]-prostate-specific membrane antigen (PSMA)-617 (177Lu-PSMA-617) followed by maintenance pembrolizumab was safe and could induce durable clinical benefit. METHODS: We did an open-label, dose-expansion, phase 1 study at the University of California, San Francisco (San Fransisco, CA, USA). Eligible patients were men aged 18 years or older with progressive metastatic castration-resistant prostate cancer who had an Eastern Cooperative Oncology Group performance status of 0 or 1, had progression on one or more androgen signalling inhibitors, and at least three PSMA-avid lesions on 68Ga-PSMA-11 positron emission tomography. In part A, patients were enrolled sequentially to one of three schedules in which a single dose of 177Lu-PSMA-617 (7·4 GBq) was given intravenously 28 days before (schedule 1), concomitant with (schedule 2), or 21 days after (schedule 3) the start of maintenance intravenous pembrolizumab (200 mg every 3 weeks). In part B, 25 patients were enrolled using the recommended phase 2 schedule. The primary endpoint in part A was determination of the recommended phase 2 schedule, and in part B, the objective response rate. The analysis set included all patients who received at least one dose of pembrolizumab or 177Lu-PSMA-617. This study is registered with ClinicalTrials.gov, NCT03805594. FINDINGS: Between Aug 8, 2019 and May 7, 2022, 43 male patients were enrolled (n=18 part A [six patients per schedule]; n=25 part B), with a median follow-up of 16·5 months (IQR 12·2-21·9). Schedule 1 was selected as the recommended phase 2 schedule for part B, on the basis of safety and feasibility of administration observed in part A. In part B, 14 (56%; 95% CI 35-76) of 25 patients had a confirmed objective response. Two (5%) of 43 patients had a treatment-related adverse event of grade 3 or worse (grade 3 arthritis in schedule 2, grade 3 pneumonitis in schedule 3). One serious adverse event (one death due to aspiration pneumonia) and no treatment-related deaths were observed. INTERPRETATION: A single priming dose of 177Lu-PSMA-617 followed by pembrolizumab maintenance was safe and had encouraging preliminary activity in patients with metastatic castration-resistant prostate cancer. FUNDING: Prostate Cancer Foundation, National Cancer Institute, Novartis Pharmaceuticals, and Merck.

Clinical and Histopathologic Characteristics of Pediatric Patients With Primary Membranous Nephropathy.

Introduction: Primary membranous nephropathy (PMN) is uncommon in children. Therefore, data on the clinical course of affected children are scarce. In recent years, several novel antigens have been implicated in the pathogenesis of PMN. However, the histopathologic characteristics of pediatric patients with PMN remain poorly represented in the literature. Methods: We have retrospectively analyzed the clinical presentation and outcomes data of 21 children with PMN from 3 centers in the United States. In addition, we have identified novel antigens in biopsy specimens from these patients and correlated their presence or absence to clinical outcomes. Finally, we compared the results of the novel antigen staining from our clinical cohort to a validation cohort of 127 biopsy specimens from children with PMN at Arkana Laboratories. Results: The data from the 2 cohorts demonstrated similar overall antigen positivity rates of 62% to 63%, with phospholipase A2 receptor (PLA2R) and exostosin 1 (EXT1) being the most commonly found antigens. Results from the clinical cohort showed that overall, the kidney prognosis for children with PMN was good, with 17 of 21 patients entering a complete or partial remission. Children who were positive for PLA2R or EXT1 were significantly more likely to enter remission than those in the antigen negative group. Conclusion: Approximately 60% of pediatric membranous cases are positive for a novel antigen on kidney biopsy and the clinical prognosis is generally favorable. More studies are needed to understand the clinical implications of each specific novel antigen.

Chemoenzymatic Syntheses of Fluorine-18-Labeled Disaccharides from [18F] FDG Yield Potent Sensors of Living Bacteria In Vivo.

Chemoenzymatic techniques have been applied extensively to pharmaceutical development, most effectively when routine synthetic methods fail. The regioselective and stereoselective construction of structurally complex glycans is an elegant application of this approach that is seldom applied to positron emission tomography (PET) tracers. We sought a method to dimerize 2-deoxy-[18F]-fluoro-d-glucose ([18F]FDG), the most common tracer used in clinical imaging, to form [18F]-labeled disaccharides for detecting microorganisms in vivo based on their bacteria-specific glycan incorporation. When [18F]FDG was reacted with ß-d-glucose-1-phosphate in the presence of maltose phosphorylase, the α-1,4- and α-1,3-linked products 2-deoxy-[18F]-fluoro-maltose ([18F]FDM) and 2-deoxy-2-[18F]-fluoro-sakebiose ([18F]FSK) were obtained. This method was further extended with the use of trehalose (α,α-1,1), laminaribiose (ß-1,3), and cellobiose (ß-1,4) phosphorylases to synthesize 2-deoxy-2-[18F]fluoro-trehalose ([18F]FDT), 2-deoxy-2-[18F]fluoro-laminaribiose ([18F]FDL), and 2-deoxy-2-[18F]fluoro-cellobiose ([18F]FDC). We subsequently tested [18F]FDM and [18F]FSK in vitro, showing accumulation by several clinically relevant pathogens including Staphylococcus aureus and Acinetobacter baumannii, and demonstrated their specific uptake in vivo. Both [18F]FDM and [18F]FSK were stable in human serum with high accumulation in preclinical infection models. The synthetic ease and high sensitivity of [18F]FDM and [18F]FSK to S. aureus including methicillin-resistant (MRSA) strains strongly justify clinical translation of these tracers to infected patients. Furthermore, this work suggests that chemoenzymatic radiosyntheses of complex [18F]FDG-derived oligomers will afford a wide array of PET radiotracers for infectious and oncologic applications.

Covalent Proteins as Targeted Radionuclide Therapies Enhance Antitumor Effects.

Molecularly targeted radionuclide therapies (TRTs) struggle with balancing efficacy and safety, as current strategies to increase tumor absorption often alter drug pharmacokinetics to prolong circulation and normal tissue irradiation. Here we report the first covalent protein TRT, which, through reacting with the target irreversibly, increases radioactive dose to the tumor without altering the drug's pharmacokinetic profile or normal tissue biodistribution. Through genetic code expansion, we engineered a latent bioreactive amino acid into a nanobody, which binds to its target protein and forms a covalent linkage via the proximity-enabled reactivity, cross-linking the target irreversibly in vitro, on cancer cells, and on tumors in vivo. The radiolabeled covalent nanobody markedly increases radioisotope levels in tumors and extends tumor residence time while maintaining rapid systemic clearance. Furthermore, the covalent nanobody conjugated to the α-emitter actinium-225 inhibits tumor growth more effectively than the noncovalent nanobody without causing tissue toxicity. Shifting the protein-based TRT from noncovalent to covalent mode, this chemical strategy improves tumor responses to TRTs and can be readily scaled to diverse protein radiopharmaceuticals engaging broad tumor targets.

Chemoenzymatic syntheses of fluorine-18-labeled disaccharides from [ 18 F]FDG yield potent sensors of living bacteria in vivo.

Chemoenzymatic techniques have been applied extensively to pharmaceutical development, most effectively when routine synthetic methods fail. The regioselective and stereoselective construction of structurally complex glycans is an elegant application of this approach, that is seldom applied to positron emission tomography (PET) tracers. We sought a method to dimerize 2-deoxy-[ 18 F]-fluoro-D-glucose ([ 18 F]FDG), the most common tracer used in clinical imaging, to form [ 18 F]-labeled disaccharides for detecting microorganisms in vivo based on their bacteria-specific glycan incorporation. When [ 18 F]FDG was reacted with ß-D-glucose-1-phosphate in the presence of maltose phosphorylase, both the α-1,4 and α-1,3-linked products 2-deoxy-[ 18 F]-fluoro-maltose ([ 18 F]FDM) and 2-deoxy-2-[ 18 F]-fluoro-sakebiose ([ 18 F]FSK) were obtained. This method was further extended with the use of trehalose (α,α-1,1), laminaribiose (ß-1,3), and cellobiose (ß-1,4) phosphorylases to synthesize 2-deoxy-2-[ 18 F]fluoro-trehalose ([ 18 F]FDT), 2-deoxy-2-[ 18 F]fluoro-laminaribiose ([ 18 F]FDL), and 2-deoxy-2-[ 18 F]fluoro-cellobiose ([ 18 F]FDC). We subsequently tested [ 18 F]FDM and [ 18 F]FSK in vitro, showing accumulation by several clinically relevant pathogens including Staphylococcus aureus and Acinetobacter baumannii, and demonstrated their specific uptake in vivo. The lead sakebiose-derived tracer [ 18 F]FSK was stable in human serum and showed high uptake in preclinical models of myositis and vertebral discitis-osteomyelitis. Both the synthetic ease, and high sensitivity of [ 18 F]FSK to S. aureus including methicillin-resistant (MRSA) strains strongly justify clinical translation of this tracer to infected patients. Furthermore, this work suggests that chemoenzymatic radiosyntheses of complex [ 18 F]FDG-derived oligomers will afford a wide array of PET radiotracers for infectious and oncologic applications.

Predictors of adverse safety events and unscheduled care among an outpatient parenteral antimicrobial therapy (OPAT) patient cohort.

Background: Select circumstances require outpatient parenteral antimicrobial therapy (OPAT). The potency of OPAT agents presents an increased risk of adverse events and unscheduled medical care. We analyzed these outcomes among OPAT recipients as part of the implementation of a collaborative OPAT program. Methods: Adult patients discharged home from an academic hospital with OPAT between January 2019 and June 2021 were included in this retrospective cohort; participants discharged between June 2020 and June 2021 were part of the collaborative OPAT program. Patients with cystic fibrosis were excluded. Data on patient characteristics and outcomes were collected from electronic medical records by two reviewers. Multivariable analysis was conducted to identify predictors of vascular access device (VAD) complications, adverse drug events (ADEs), and OPAT-related emergency department (ED) visits and rehospitalizations. Results: Among 265 patients included in the cohort, 57 (21.5%) patients experienced a VAD complication; obesity [odds ratio (OR): 3.32; 95% confidence interval (CI): 1.38-8.73; p = 0.01) and multi-drug therapy (OR: 2.56; 95% CI: 1.21-5.39; p = 0.01) were associated with an increased odds of VAD complication. Eighty-two (30.9%) participants experienced an ADE; 30 (11.3%) experienced a severe/serious ADE. Lipo/glycopeptide receipt, (OR: 5.28; 95% CI: 1.89-15.43; p < 0.01) and Black/African American race (OR: 4.85; 95% (CI): 1.56-15.45; p < 0.01) were associated with an increased odds of severe/serious ADE. Inclusion in the OPAT collaborative was associated with a decreased odds of severe/serious ADE (OR: 0.26; 95% CI: 0.08-0.77; p = 0.01). Fifty-eight (21.9%) patients experienced an OPAT-related ED visit and 53 (20.0%) experienced an OPAT-related rehospitalization. VAD complication (OR: 2.37; 95% (CI): 1.15-4.86, p = 0.02) and ADEs (OR: 2.19; CI: 1.13-4.22; p = 0.02) were associated with OPAT-related ED visits. ADE was associated with 90-day OPAT-related rehospitalization (OR: 3.21; (CI): 1.59-6.58; p < 0.01). Conclusion: Adverse safety events and OPAT-related unscheduled care occurred often in our cohort. A structured OPAT program that includes ID pharmacist antibiotic reconciliation may reduce rates of ADEs.

Evaluation of Dosimetry Formalisms in Intraoperative Radiation Therapy of Glioblastoma.

PURPOSE: The intraoperative radiotherapy in newly diagnosed glioblastoma multiforme (INTRAGO) clinical trial assesses survival in patients with glioblastoma treated with intraoperative radiation therapy (IORT) using the INTRABEAM. Treatment planning for INTRABEAM relies on vendor-provided in-water depth dose curves obtained according to the TARGeted Intraoperative radioTherapy (TARGIT) dosimetry protocol. However, recent studies have shown discrepancies between the estimated TARGIT and delivered doses. This work evaluates the effect of the choice of dosimetry formalism on organs at risk (OAR) doses. METHODS AND MATERIALS: A treatment planning framework for INTRABEAM was developed to retrospectively calculate the IORT dose in 8 INTRAGO patients. These patients received an IORT prescription dose of 20 to 30 Gy in addition to external beam radiation therapy. The IORT dose was obtained using (1) the TARGIT method; (2) the manufacturer's V4.0 method; (3) the CQ method, which uses an ionization chamber Monte Carlo (MC) calculated factor; (4) MC dose-to-water; and (5) MC dose-to-tissue. The IORT dose was converted to 2 Gy fractions equivalent dose. RESULTS: According to the TARGIT method, the OAR dose constraints were respected in all cases. However, the other formalisms estimated a higher mean dose to OARs and revealed 1 case where the constraint for the brain stem was exceeded. The addition of the external beam radiation therapy and TARGIT IORT doses resulted in 10 cases of OARs exceeding the dose constraints. The more accurate MC calculation of dose-to-tissue led to the highest dosimetric differences, with 3, 3, 2, and 2 cases (out of 8) exceeding the dose constraint to the brain stem, optic chiasm, optic nerves, and lenses, respectively. Moreover, the mean cumulative dose to brain stem exceeded its constraint of 66 Gy with the MC dose-to-tissue method, which was not evident with the current INTRAGO clinical practice. CONCLUSIONS: The current clinical approach of calculating the IORT dose with the TARGIT method may considerably underestimate doses to nearby OARs. In practice, OAR dose constraints may have been exceeded, as revealed by more accurate methods.

Prolonged Elevations of Factor VIII and von Willebrand Factor Antigen After Multisystem Inflammatory Syndrome in Children.

Multisystem Inflammatory Syndrome in Children (MIS-C) is a late systemic inflammatory response to a recent mild or asymptomatic coronavirus disease of 2019 infection. The pathophysiology is incompletely understood but it often features significant coagulopathy along with cardiac and endothelial dysfunction. Endothelial inflammation has been primarily described in acute coronavirus disease of 2019 infection, with less characterization in MIS-C. Here we describe novel findings of nearly universal severe and prolonged factor VIII (FVIII) and von Willebrand factor antigen elevations in an institutional cohort of patients with MIS-C ages younger than or 21 years old (N=31). All patients had elevated acute phase reactants and D-dimer at presentation and met published criteria for MIS-C. FVIII was high at presentation in 97% of patients but continued to rise during the ensuing weeks of treatment to a mean 429%, peaking on median day 17 of illness as an outpatient. FVIII levels were >600% in multiple patients. von Willebrand factor antigen was measured less frequently but showed similar trends. These escalations occurred amidst resolving cardiac dysfunction and acute phase reactant normalization and despite patients receiving multimodal anti-inflammatory treatments and aspirin and enoxaparin thromboprophylaxis. No thrombotic events occurred. Endothelial dysfunction represented by very elevated FVIII levels may persist longer than other acute phase reactants may reflect.

Elevated labile iron in castration-resistant prostate cancer is targetable with ferrous iron-activatable antiandrogen therapy.

Clinical responses to second generation androgen signaling inhibitors (e.g., enzalutamide) in metastatic castration-resistant prostate cancer (mCRPC) are variable and transient, and are associated with dose limiting toxicities, including rare but severe CNS effects. We hypothesized that changes to iron metabolism coincident with more advanced disease might be leveraged for tumor-selective delivery of antiandrogen therapy. Using the recently described chemical probes SiRhoNox and 18F-TRX in mCRPC models, we found elevated Fe2+ to be a common feature of mCRPC in vitro and in vivo. We next synthesized ferrous-iron activatable drug conjugates of second and third-generation antiandrogens and found these conjugates possessed comparable or enhanced antiproliferative activity across mCRPC cell line models. Mouse pharmacokinetic studies showed that these prototype antiandrogen conjugates are stable in vivo and limited exposure to conjugate or free antiandrogen in the brain. Our results reveal elevated Fe2+ to be a feature of mCRPC that might be leveraged to improve the tolerability and efficacy of antiandrogen therapy.

Theranostic Targeting of CUB Domain-Containing Protein 1 (CDCP1) in Multiple Subtypes of Bladder Cancer.

PURPOSE: Despite recent approvals for checkpoint inhibitors and antibody-drug conjugates targeting NECTIN4 or TROP2, metastatic bladder cancer remains incurable and new treatment strategies are urgently needed. CUB domain-containing protein 1 (CDCP1) is a cell surface protein and promising drug target for many cancers. This study aimed to determine whether CDCP1 is expressed in bladder cancer and whether CDCP1 can be targeted for treatment with radiolabeled antibodies. EXPERIMENTAL DESIGN: CDCP1 expression was evaluated in four bladder cancer datasets (n = 1,047 biopsies). A tissue microarray of primary bladder cancer biopsies was probed for CDCP1 by IHC. CDCP1 expression was evaluated in patient-derived xenografts and cell lysates by immunoblot, flow cytometry, and saturation binding assays. Tumor detection in mouse bladder cancer models was tested using 89Zr-labeled 4A06, a monoclonal antibody targeting the ectodomain of CDCP1. 177Lu-4A06 was applied to mice bearing UMUC3 or HT-1376 xenografts to evaluate antitumor effects (CDCP1 expression in UMUC3 is 10-fold higher than HT-1376). RESULTS: CDCP1 was highest in the basal/squamous subtype, and CDCP1 was expressed in 53% of primary biopsies. CDCP1 was not correlated with pathologic or tumor stage, metastatic site, or NECTIN4 and TROP2 at the mRNA or protein level. CDCP1 ranged from 105 to 106 receptors per cell. Mechanism studies showed that RAS signaling induced CDCP1 expression. 89Zr-4A06 PET detected five human bladder cancer xenografts. 177Lu-4A06 inhibited the growth of UMUC3 and HT-1376 xenografts, models with high and moderate CDCP1 expression, respectively. CONCLUSIONS: These data establish that CDCP1 is expressed in bladder cancer, including TROP2 and NECTIN4-null disease, and suggest that bladder cancer can be treated with CDCP1-targeted radiotherapy.

The mixed spongiotic and interface reaction pattern: A study of clinical and histopathologic findings.

BACKGROUND: Categorization of biopsy specimens into inflammatory reaction patterns is central to dermatopathologic assessment. Mixed inflammatory patterns are poorly characterized and may represent clinicopathologic challenges. The purpose of this study was to identify clinical and histopathologic findings associated with the mixed spongiotic-interface dermatitis (SID) histopathologic pattern. METHODS: Fifty-one institutional biopsy specimens of SID were identified over a 2-year period by retrospective natural language search. Histopathologic and clinical features were identified. RESULTS: The most common histopathologic features associated with SID were mild spongiosis (51%), focal vacuolar interface change (72%), lymphocytic exocytosis (92%), and superficial-dermal lymphocytic infiltrate (94%) with variable eosinophils (61%). Clinically, 80% of subjects presented with a symmetric morbilliform eruption. Polypharmacy (94%), immunosuppression (47%), and history of malignancy (47%) were common. The most common diagnoses were drug reaction (37%), possible drug reaction (12%), and viral exanthem (12%). Drug reaction with eosinophilia and systemic symptoms represented 25% of all confirmed cutaneous adverse drug reactions (CADR). Average time from drug initiation to symptom initiation was 20 days (SD: 22.3, range: 0-90); median disease duration was 25.5 days. Spongiotic vesicles and Langerhans cells were less common in patients with a strong clinicopathologic diagnosis of drug reaction compared to non-drug eruptions (p = 0.04). CONCLUSIONS: The mixed SID pattern is commonly encountered in CADR but may represent a more subacute course, implying consideration for inciting medication(s) started before the typical 7- to 14-day window.

Impact of Radiolabeling Strategies on the Pharmacokinetics and Distribution of an Anti-PD-L1 PET Ligand.

Molecular imaging with PET offers an alternative method to quantify programmed-death-ligand 1 (PD-L1) to accurately select patients for immunotherapies. More and more clinical and preclinical trials involve radiolabeling of antibody fragments for their desirably fast clearance and high tumor penetration. As the radiolabeling strategy can significantly impact pharmacokinetics and biodistribution, we explored in this work a site-specific radiofluorination strategy on an anti-PD-L1 fragment antigen-binding (Fab) and compared the pharmacokinetic and biodistribution properties with the same Fab labeled using stochastic radiolabeling chemistry. We applied an enzymatic bioconjugation mediated by a variant of the lipoic acid ligase (LplA) that promotes the formation of an amide bond between a short peptide cloned onto the C terminus of the Fab. A synthetic analogue of the enzyme natural substrate, lipoic acid, was radiolabeled with fluorine-18 for site-specific conjugation by LplA. We compared the biodistribution of the site-specifically labeled Fab with a stochastically labeled Fab on lysine side chains in tumor-bearing mice. The two methods of fluorination demonstrate a comparable whole-body biodistribution. The 89Zr-labeled Fab had different biodistribution compared to either 18F-labeled Fab. We attribute the difference to [89Zr] metabolism. Fab-LAP-[18F]FPyOctA therefore reflects better the true pharmacokinetic profile of the Fab.

Health Information Technology Use among Chronic Disease Patients: An Analysis of the United States Health Information National Trends Survey.

BACKGROUND: Chronic disease is the leading cause of mortality in the United States. Health information technology (HIT) tools show promise for improving disease management. OBJECTIVES: This study aims to understand the following: (1) how self-perceptions of health compare between those with and without disease; (2) how HIT usage varies between chronic disease profiles (diabetes, hypertension, cardiovascular disease, pulmonary disease, depression, cancer, and comorbidities); (3) how HIT trends have changed in the past 6 years; and (4) the likelihood that a given chronic disease patient uses specific HIT tools. METHODS: The Health Information National Trends Survey (HINTS) inclusive of 2014 to 2020 served as the primary data source with statistical analysis completed using Stata. Bivariate analyses and two-tailed t-tests were conducted to compare self-perceived health and HIT usage to chronic disease. Logistic regression models were created to examine the odds of a specific patient using various forms of HIT, controlling for demographics and comorbidities. RESULTS: Logistic regression models controlling for sociodemographic factors and comorbidities showed that pulmonary disease, depression, and cancer patients had an increased likelihood of using HIT tools, for example, depression patients had an 81.1% increased likelihood of looking up health information (p < 0.0001). In contrast, diabetic, high blood pressure, and cardiovascular disease patients appeared to use HIT tools at similar rates to patients without chronic disease. Overall HIT usage has increased during the timeframe examined. CONCLUSION: This study demonstrates that certain chronic disease cohorts appear to have greater HIT usage than others. Further analysis should be done to understand what factors influence patients to utilize HIT which may provide additional insights into improving design and user experience for other populations with the goal of improving management of disease. Such analyses could also establish a new baseline to account for differences in HIT usage as a direct consequence of the novel coronavirus disease 2019 (COVID-19) pandemic.

Defining the Magnetic Resonance Features of Renal Lesions and Their Response to Everolimus in a Transgenic Mouse Model of Tuberous Sclerosis Complex.

Tuberous sclerosis complex (TSC) is an inherited genetic disorder characterized by mutations in TSC1 or TSC2 class of tumor suppressers which impact several organs including the kidney. The renal manifestations are usually in the form of angiomyolipoma (AML, in 80% of the cases) and cystadenomas. mTOR inhibitors such as rapamycin and everolimus have shown efficacy in reducing the renal tumor burden. Early treatment prevents the progression of AML; however, the tumors regrow upon cessation of therapy implying a lifelong need for monitoring and management of this morbid disease. There is a critical need for development of imaging strategies to monitor response to therapy and progression of disease which will also facilitate development of newer targeted therapy. In this study we evaluated the potential of multiparametric 1H magnetic resonance imaging (mpMRI) to monitor tumor response to therapy in a preclinical model of TSC, the transgenic mouse A/J Tsc2+/- . We found 2-dimensional T2-weighted sequence with 0.5 mm slice thickness to be optimal for detecting renal lesions as small as 0.016 mm3. Baseline characterization of lesions with MRI to assess physiological parameters such as cellularity and perfusion is critical for distinguishing between cystic and solid lesions. Everolimus treatment for three weeks maintained tumor growth at 36% from baseline, while control tumors displayed steady growth and were 70% larger than baseline at the end of therapy. Apparent diffusion coefficient, T1 values and normalized T2 intensity changes were also indictive of response to treatment. Our results indicate that standardization and implementation of improved MR imaging protocols will significantly enhance the utility of mpMRI in determining the severity and composition of renal lesions for better treatment planning.