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Mild hyperthermia (MHTh) is often used in combination with chemotherapy and radiotherapy for cancer treatment. In the current study, the effect of MHTh on the enhanced uptake of the FDA-approved chemotherapy drug, liposomal doxorubicin (dox) in syngeneic 4T1 tumors was investigated. Doxorubicin has inherent fluorescence properties having an emission signal at 590 nm upon excitation with a 480 nm laser. A group of mice administered with doxorubicin (dox) were exposed to MHTh (42 °C) for 30 minutes whereas control group given dox did not receive MHTh. Ex vivo optical imaging of harvested tumors confirmed higher uptake of dox in treated versus the control untreated tumors. Confocal microscopy of tumor sections indicates higher fluorescent intensity due to increased accumulation of dox in MHTh-treated compared to untreated tumors. We examined the effect of MHTh to enhance CD8 tumor infiltration, production of interferon-γ (IFN-γ) and expression of programmed death ligand-1 (PD-L1). mRNA in situ hybridization was performed to test for transcripts of CD8, IFN-γ and PD-L1. Results showed that higher expression of CD8 mRNA was observed in MHTh-administered tumors versus untreated cohorts. The signal for IFN-γ and PD-L1 in both groups were not significantly different. Taken together, our findings imply that MHTh can improve tumor uptake of dox. Importantly, our data suggests that MHTh can boost CD8+ T cell infiltration.

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INTRODUCTION: Shoulder injuries account for approximately 8% to 24% of all musculoskeletal injuries in the military. Recently, a change was made to service-specific physical fitness tests. Knowledge of relative shoulder labral injury rates before and after this change would help guide future directions and preventive strategies. However, we found no previous literature evaluating the rates of labral injury among United States Military branch personnel by enlistment status (enlisted versus officer), gender, age, or race. MATERIALS AND METHODS: In this retrospective epidemiological study, we queried the Defense Medical Epidemiology Database for International Classification of Disease, Tenth Revision (ICD-10) code S43.43 (superior glenoid labrum lesion) to determine the total number of patients with a shoulder labral injury from 2016 to 2019. Results were assessed for demographic associations of shoulder labral injury with branch, service occupation, rank, gender, race, and age. Queries were limited to first-time occurrences and ambulatory data only. RESULTS: Overall, our study found the incidence of shoulder labral injuries to be largely conserved each year from 2016 to 2019 (3.22-3.35/1000/year). Incidence of labral injury was highest in males, White service members, the junior enlisted, the Army service branch, ages 20 to 29, and enlisted non-combat personnel. CONCLUSIONS: With knowledge of injury patterns in specific military populations, initiatives may be taken to identify at-risk service members with the goal of informing future preventive strategies.

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Inflammatory bowel disease (IBD), which includes both Crohn disease and ulcerative colitis, is a relapsing inflammatory disease of the gastrointestinal tract. Long-term chronic inflammatory conditions elevate the patient's risk of colorectal cancer (CRC). Currently, diagnosis requires endoscopy with biopsy. This procedure is invasive and requires a bowel-preparatory regimen, adding to patient burden. Interleukin 12 (IL12) and interleukin 23 (IL23) play key roles in inflammation, especially in the pathogenesis of IBD, and are established therapeutic targets. We propose that imaging of IL12/23 and its p40 subunit in IBD via immuno-PET potentially provides a new noninvasive diagnostic approach. Methods: Our aim was to investigate the potential of immuno-PET to image inflammation in a chemically induced mouse model of colitis using dextran sodium sulfate by targeting IL12/23p40 with a 89Zr-radiolabeled anti-IL12/23p40 antibody. Results: High uptake of the IL12/23p40 immuno-PET agent was exhibited by dextran sodium sulfate-administered mice, and this uptake correlated with increased IL12/23p40 present in the sera. Competitive binding studies confirmed the specificity of the radiotracer for IL12/23p40 in the gastrointestinal tract. Conclusion: These promising results demonstrate the utility of this radiotracer as an imaging biomarker of IBD. Moreover, IL12/23p40 immuno-PET can potentially guide treatment decisions for IBD management.

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Purpose: TRA-1-60 (TRA) is an established transcription factor of embryonic signaling and a well-known marker of pluripotency. It has been implicated in tumorigenesis and metastases, is not expressed in differentiated cells, which makes it an appealing biomarker for immunopositron emission tomography (immunoPET) imaging and radiopharmaceutical therapy (RPT). Herein, we explored the clinical implications of TRA in prostate cancer (PCa), examined the potential of TRA-targeted PET to specifically image TRA+ cancer stem cells (CSCs) and assessed response to the selective ablation of PCa CSCs using TRA-targeted RPT. Experimental Design: First, we assessed the relationship between TRA (PODXL) copy number alterations (CNA) and survival using publicly available patient databases. The anti-TRA antibody, Bstrongomab, was radiolabeled with Zr-89 or Lu-177 for immunoPET imaging and RPT in PCa xenografts. Radiosensitive tissues were collected to assess radiotoxicity while excised tumors were examined for pathologic treatment response. Results: Patients with tumors having high PODXL CNA exhibited poorer progression-free survival than those with low PODXL, suggesting that it plays an important role in tumor aggressiveness. TRA-targeted immunoPET imaging specifically imaged CSCs in DU-145 xenografts. Tumors treated with TRA RPT exhibited delayed growth and decreased proliferative activity, marked by Ki-67 immunohistochemistry. Aside from minor weight loss in select animals, no significant signs of radiotoxicity were observed in the kidneys or livers. Conclusions: We successfully demonstrated the clinical significance of TRA expression in human PCa, engineered and tested radiotheranostic agents to image and treat TRA+ prostate CSCs. Ablation of TRA+ CSCs blunted PCa growth. Future studies combining CSC ablation with standard treatment will be explored to achieve durable responses.

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INTRODUCTION: Interferon-γ (IFN-γ) is an appealing target to evaluate immune response in cancer immunotherapy as it is a hallmark of an active immune system. Imaging and detection via immunopositron emission tomography (immunoPET) of this soluble cytokine has been made feasible using a 89Zr-labeled (t 1/2 ~ 3.27 d) monoclonal antibody (mAb). Because of its size, using a full-length mAb as an imaging vector is not ideal for repeat serial imaging because of its prolonged blood pool residency and tumor accumulation resulting in lengthier wait times between administration and imaging. This consequently impacts the potential to image a dynamic immune response in real time. This work compares 89Zr-labeled diabodies (Db) designed with variable linker lengths between the VH and VL regions with the goal of selecting a lead Db for future studies. METHODS AND RESULTS: Four Db fragments with various linker lengths (HL-n, n = 7-13 amino acids) were each conjugated to desferrioxamine (DFO). The number of attached chelates was analyzed via mass spectrometry with all immunoconjugates exhibiting one unit of DFO attached. Db-DFO conjugates were subsequently radiolabeled with zirconium-89. All constructs radiolabeled with high yields. Each radioimmunoconjugate was tested for reactivity to IFN-γ. All tracers except for [89Zr]Zr-DFO-NCS-anti-IFN-γ HL-9 exhibited comparable immunoreactivities (>90 %) to the radiolabeled parent mAb (95.8 %). At 24 h post-labeling, the IRF values were retained except for the HL-13 construct. Imaging scans and tissue distribution studies acquired in mice bearing CT26 syngeneic colorectal tumors between 1 and 24 h post-tracer administration demonstrated variable clearance kinetics and tumor localization of each radiotracer. HL-7 had higher binding in non-tumor tissues compared to HL-11 and HL-13 at 3 h p.i. Competitive binding studies versus unmodified parent mAb (AN-18) demonstrated blocking of radiolabeled HL-11 and HL-13. [89Zr]Zr-DFO-NCS-anti-IFN-γ HL-7 was inadequately blocked. CONCLUSION: Despite nuanced differences in linker lengths, our data demonstrates that [89Zr]Zr-DFO-NCS-anti-IFN-γ HL-11 exhibited the best radiotracer properties for the assessment of IFN-γ production in vivo. Work is currently underway to test the potential of using shorter-lived isotopes, like copper-64 (t1/2 ~ 12.7 h) to match pharmacokinetics and half-lives.

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The autophagy-lysosome pathway and apoptosis constitute vital determinants of cell fate and engage in a complex interplay in both physiological and pathological conditions. Central to this interplay is the archetypal autophagic cargo adaptor p62/SQSTM1/Sequestosome-1 which mediates both cell survival and endoplasmic reticulum stress-induced apoptosis via aggregation of ubiquitinated caspase-8. Here, we investigated the role of p62-mediated apoptosis in head and neck squamous cell carcinoma (HNSCC), which can be divided into two groups based on human papillomavirus (HPV) infection status. We show that increased autophagic flux and defective apoptosis are associated with radioresistance in HPV(-) HNSCC, whereas HPV(+) HNSCC fail to induce autophagic flux and readily undergo apoptotic cell death upon radiation treatments. The degree of radioresistance and tumor progression of HPV(-) HNSCC respectively correlated with autophagic activity and cytosolic levels of p62. Pharmacological activation of the p62-ZZ domain using small molecule ligands sensitized radioresistant HPV(-) HNSCC cells to ionizing radiation by facilitating p62 self-polymerization and sequestration of cargoes leading to apoptosis. The self-polymerizing activity of p62 was identified as the essential mechanism by which ubiquitinated caspase-8 is sequestered into aggresome-like structures, without which irradiation fails to induce apoptosis in HNSCC. Our results suggest that harnessing p62-dependent sequestration of ubiquitinated caspase-8 provides a novel therapeutic avenue in patients with radioresistant tumors.

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Techniques for reconstruction of posterior cruciate ligament (PCL) tears are rapidly evolving. One problem with current techniques is that laxity may develop early in the postoperative period, leading to relapsed posterior translation of the tibia. Therefore, maintaining tibial reduction during graft incorporation is a target for improvement. We describe using an internal splint to optimize the 4-tunnel, double-bundle allograft PCL reconstruction.

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OBJECTIVE: To compare the clinical and radiographic outcomes between patients treated with fibula allograft-augmented locking compression fixation and patients treated with locking compression fixation alone for 2- and 3-part proximal humeral fractures with varus displacement. DESIGN: Retrospective review. SETTING: Level 1 trauma center. PATIENTS/PARTICIPANTS: One hundred two patients treated with locking plate fixation ± fibular allograft augmentation confirmed intraoperatively by visual inspection to have varus-angulated, 2- and 3-part proximal humerus fractures with at least 45 degrees of varus angulation at the neck/shaft and at least 1 cm of displacement. INTERVENTION: Proximal humerus locking plate (PHILOS; Synthes, Paoli, PA) with or without fibula allograft augmentation. MAIN OUTCOME MEASUREMENTS: Statistical analysis to determine the differences between fractures treated with locking compression fixation ± fibula allograft augmentation regarding complications, shoulder reported outcome measures, and patient ROMs (Visual Analog Score (VAS), Disabilities of the Arm, Shoulder and Hand, and Simple Shoulder Test scores). Medical comorbidities as potential risk factors for complication from surgery were also evaluated. RESULTS: Of 102 surgical cases, 27 were augmented with fibula allograft and 75 were not. Postoperatively, there were 16 noncatastrophic varus collapses of the fracture, 6 catastrophic varus collapses, and 5 deaths. Addition of fibula allograft did not significantly affect postoperative varus collapse, shoulder ROM, pain, or PROMs. CONCLUSION: Addition of fibula allograft to patients sustaining varus-angulated, 2- and 3-part proximal humeral fractures conferred no benefit to patient outcomes at our institution. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

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BACKGROUND: Perioperative glucocorticoids are routinely administered to patients undergoing total joint arthroplasty (TJA) to decrease postoperative pain and nausea. However, there is concern regarding the effects of glucocorticoids on perioperative glucose control in diabetes. The goal of this study is to determine if administration of preoperative dexamethasone to diabetic patients is significantly associated with hyperglycemia and increased insulin requirements in the immediate postoperative period after TJA and to identify risk factors for postoperative hyperglycemia immediately after TJA. METHODS: A retrospective review of type 2 diabetic patients undergoing TJA from 2010 to 2015 (n = 285) was undertaken to evaluate the effect of dexamethasone on postoperative glucose control. Preoperative baseline characteristics were compared between patients who did and did not receive 8 mg of intravenous dexamethasone preoperatively. Postoperative glucose and insulin requirements were evaluated with respect to dexamethasone dosing. Statistical analysis was performed using logistic regression models. RESULTS: Dexamethasone administration did not correlate with the maximum postoperative blood glucose (P = .78). There was a significantly higher initial postoperative blood glucose after intravenous dexamethasone administration (P < .01). Dexamethasone administration was associated with increased aspart insulin requirements on postoperative day 0 (P = .04). However, preoperative hemoglobin A1c was most strongly associated with postoperative glucose control. CONCLUSION: Preoperative dexamethasone administration to diabetic patients was associated with an initial increase in blood glucose and increased insulin requirement on postoperative day 0. Yet the observed effect on glucose control in diabetic patients may not outweigh the known clinical benefits of perioperative glucocorticoids.

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