Citations

Abstract Description Therapies targeting the PD-1/PD-L1 axis are among the leading treatments of cancer, but only a minority of patients benefit. Many therapies focus on preventing PD-L1 from binding to its receptor, PD-1, but do not address PD-L1’s ability to be recycled to the cell surface and any intrinsic functions it may possess. Our lab has developed an antibody (H1A) that binds to PD-L1 and prevents its association with a stabilizing protein, CMTM6, therefore targeting it for lysosomal degradation. Consequently, H1A limits any PD-L1 intrinsic function while also decreasing interactions with PD-1. Here, we use human-derived immune cells to test H1A’s effect on immune responses through flow cytometry, multiplex screening, and cytotoxicity assays. Additionally, we have developed a humanized PD-1/PD-L1 mouse model that allows us to test H1A’s effect on tumor growth inhibition in an immunocompetent host. Our results show that H1A specifically targets human myeloid cells, resulting in increased co-stimulation, antigen presentation, and cytokine secretion. H1A demonstrated enhanced T cell cytotoxicity in a whole PBMC culture. Finally, H1A resulted in greater tumor growth inhibition and survival in our in vivo tumor models. This work highlights the importance of targeting beyond PD-1/PD-L1 ligation and that myeloid cells are instrumental to enhancing the immune response against cancer. H1A is emerging as a new immunotherapy tool to target PD-L1 and CMTM6 in myeloid cells for treatment of cancers. Funding Sources NIH R01 92389022; NIH T32 AI170478; Mayo Clinic Graduate School of Biomedical Sciences Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)

The role of circulating tumor DNA (ctDNA) in gastroesophageal adenocarcinoma (GEA) has expanded in recent years. In resectable disease, postoperative ctDNA is able to detect patients at highest risk of recurrence months before scans. Tumor-informed assays provide the best sensitivity and emerging methylation assays are useful when tissue is scarce. In metastatic GEA, baseline ctDNA burden correlates with prognosis, and a decrease in ctDNA level after treatment initiation reflects therapeutic response. It can also uncover actionable targets, including ERBB2, FGFR2, and MSI-H, and detect resistance that can arise after starting treatment. Limitations include variable assay performance, low shedding in some tumors, clonal hematopoiesis confounding, and a lack of randomized data showing that ctDNA-guided changes improve outcomes. Ongoing trials are testing MRD-guided escalation/de-escalation and ctDNA-directed biomarker therapy. In this review, we evaluate the role of ctDNA in GEA cancers over recent years.

Abstract Introduction Penile augmentation or penis enlargement surgery refers to any technique aimed at enhancing penile length or girth. These male enhancement surgical techniques can increase total penile length, either flaccid or erect, while others add to the penile shaft’s girth and/or glans size. Proposed strategies include physical methods such as various penile exercises, mechanical traction devices, and medical therapy, while surgical interventions include cosmetic and phallic reconstructive techniques and use of fillers, sleeves, grafts, and flaps to augment penile size. Objectives The International Consultation on Sexual Medicine (ICSM) consensus statements provide evidence-based recommendations and aim to guide a clinical framework in penile aesthetic and augmentation. Methods A comprehensive literature search was conducted to identify published literature relevant to penile augmentation or enhancement. Preliminary consensus was presented to the delegates attending the 5th ICSM meeting, and feedback was incorporated into the final document. Results Twenty new recommendations are provided with corresponding levels of evidence and grades of recommendation. Conclusions Due to the controversies and lack of longer-term data regarding penile augmentation and cosmetic procedures, comprehensive assessments and careful patient counseling weighing the pros and cons, as well as potential complications, are mandatory before embarking on any treatment. Surgeons should be experienced in anatomy and various surgical techniques, and it is important to individualize surgical options based on patient condition(s) and needs, surgeon expertise, and local resources.

Abstract Introduction There is no ideal treatment for Peyronie’s Disease (PD) since every patient has different needs with varying perceived risks versus benefits of individual treatment options, coupled with the degree of impact relating to PD on sexual function and beyond. Objectives The 5th International Consultation on Sexual Medicine (ICSM) guideline on PD provides an update to the previous ICSM with an aim to provide a clinical framework and best-evidenced consensus recommendations to assist clinicians in managing PD. Methodology Available literature was reviewed, and a modified Delphi consensus was undertaken by leading sexual medicine experts to achieve a set of Quality of Evidence and strength of recommendations. This guideline was developed as an authoritative best-evidenced consensus incorporating state-of-the-art knowledge and contemporary literature. Results A total of thirty-one recommendations were made on PD guidelines. New updates to the 4th ICSM on PD have been made in definition, pathophysiology, and treatment strategies. The presence of penile pain with erection could occur in the chronic phase due to torque or stretch on the penile scar and surrounding tissue. Oral therapy works best during the acute phase and should be provided concurrently with other treatment modalities. Penile traction therapy can reduce penile deformity as monotherapy or may be offered as part of a multimodal therapy approach. There is no convincing evidence supporting cellular-based therapy. The type of plication procedure used depends on the surgeon and patient preference, although excision of the tunica followed by plication may have a higher complication rate. There is currently no ideal graft, and graft contracture can occur postoperatively. Adjunctive procedures such as penile modeling, tunical plication, plaque incision/excision and grafting can be performed when penile deformity and/or penile curvature persist following penile prosthesis implantation. Conclusions The management of PD should be individualized based on the patient’s needs and preferences while balancing the benefits and risks of each treatment option.

Background: Patellofemoral dislocations are often associated with chondral injuries. In adults, diagnostic arthroscopy (DA) has identified chondral injuries in up to one-third of cases where magnetic resonance imaging (MRI) was negative. However, the value of DA in detecting cartilage injuries in pediatric patients undergoing medial patellofemoral ligament reconstruction (MPFLR) has not been well studied. Purposes: To evaluate the utility of DA in diagnosing cartilaginous injuries in pediatric patients undergoing MPFLR with negative preoperative MRI findings and to compare postoperative outcomes between patients with and without chondral injury findings on DA. Study Design: Cohort study (diagnosis); Level of evidence, 3. Methods: A retrospective review was conducted on patients aged 0 to 18 years who underwent combined MPFLR and DA procedures from 2015 to 2023 at a single institution. The exclusion criteria were as follows: revision MPFLR; tibial tubercle osteotomy; multiligament reconstructions; and previous meniscal injury. MRI and DA reports were reviewed for chondral findings. Patients were classified into 3 groups: +MRI/+DA, –MRI/+DA, and –MRI/–DA. Subgroup analysis was performed within the –MRI/+DA group to compare outcomes in the immediate postoperative recovery period between those who underwent a chondroplasty versus those who did not. Results: Of the 155 patients included, follow-up averaged 7.8 months (median, 5 months [range, 0-41 months]). Among 89 patients with negative MRI findings, 39 (43.8%) had chondral injuries detected on DA. Targeted treatment was performed in 22 (56.4%) of these patients, a lower rate than in those with positive MRI findings (80.3%; P = .02). No significant differences were observed in knee flexion at 2 weeks postoperatively: +MRI/+DA (77.9°± 23°), –MRI/+DA (66.5°± 30.2°), and –MRI/–DA (73.3°± 30°) ( P = .14). Similarly, no significant differences were found at 12 weeks: +MRI/+DA (135.3°± 13°), –MRI/+DA (127.8°± 21°), and –MRI/–DA (134.1°± 13.4°) ( P = .10). Range of motion and complication rates were comparable across all groups ( P > .05). A subgroup analysis in the –MRI/+DA cohort comparing patients who underwent an arthroscopic procedure (n = 22) with those who did not (n = 17) showed no significant differences in range of motion or complication rates ( P > .05). Conclusion: Diagnostic arthroscopy detected cartilaginous injuries in 43.8% of pediatric patients with negative preoperative MRI undergoing MPFLR. This highlights the diagnostic value of DA in identifying injuries that would otherwise remain undetected.

Introduction: Ureteroscopy (URS) is the most commonly performed surgery for the management of renal stones. Post-URS sepsis has been reported to be around 5%, but most studies rely on purchased datasets or electronic medical record (EMR) data that pull data based on billing codes of sepsis without clinical verifications. This study aims to evaluate the true incidence of sepsis using the Sepsis-3 criteria at a single tertiary care institution. Methods: A retrospective review was conducted on all URS procedures at a single tertiary care institution from 2021 to 2022, including both Medicare and private insurance patients ≥18 years old. The EMR was queried for URS procedure codes and readmission within 30 days post-procedure with a sepsis diagnosis code. All other procedures, including URS during percutaneous nephrolithotomy, were excluded. Each identified case was evaluated for sepsis using the Sepsis-3 criteria, including sequential organ failure assessment (SOFA) and quick SOFA (qSOFA). Results: A total of 1316 patients underwent URS. Nineteen patients were identified with a sepsis diagnosis, giving an initial post-URS sepsis rate of 1.44%. After EMR verification, 5 patients were excluded, leaving 14 (1.06%) patients with a diagnosis code of sepsis. Using Sepsis-3 criteria, only 6 (0.44%) met the diagnosis. Conclusions: This retrospective review identified only 0.44% of patients with a true post-URS sepsis within 30 days using Sepsis-3 criteria. The difference in our rate from the initial query and current literature highlights the need for accurate clinical diagnosis and documentation of sepsis.

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with exposure to repetitive head impacts (RHI). In CTE, hyperphosphorylated tau (p-tau) aggregates are found in neurons at the depth of cortical sulci close to the gray matter/white matter (GM/WM) boundary. To date, CTE can only be diagnosed postmortem by neuropathological examination. Traumatic encephalopathy syndrome (TES) is the clinical syndrome purported to be associated with CTE pathology. The aim of this study is to investigate microstructural properties at the GM/WM boundary in individuals with a history of exposure to RHI and clinical features of CTE (i.e., TES). Diffusion magnetic resonance imaging (dMRI), TES diagnoses, and cerebrospinal fluid (CSF) biomarkers were acquired from 165 male former American football players (age: 57.29 ± 8.23 years) from the DIAGNOSE CTE Research Project, a multicenter, observational cohort study. Fractional anisotropy (FA) was measured at the GM/WM boundary of the whole brain. In addition, a widely used method (tract-based spatial statistics [TBSS]) was applied to measure FA of central WM. We used analyses of covariance to test associations between FA and TES. Furthermore, we used linear regressions to test associations between FA and nine CSF biomarkers (i.e., p-tau-181, -217, -231, total tau, amyloid β [Aβ] 1–40 , Aβ 1–42 , glial fibrillary acidic protein [GFAP], neurofilament light [NfL], and soluble triggering receptor expressed on myeloid cells-2 [sTREM2]). We report an association between higher FA at the GM/WM boundary and higher levels of certainty for CTE pathology ( F (1, 147) = 5.781, 95% confidence interval (CI) = 0.0003–0.003, p = 0.035) as well as neurobehavioral dysregulation ( F (1, 148) = 7.559, 95% CI = 0.001–0.009, p = 0.020), and functional dependence/dementia ( F (1, 148) = 5.046, 95% CI = 0.0004–0.006, p = 0.039). In addition, we report an association between higher FA at the GM/WM boundary and higher CSF p-tau-181 (β = 0.272, 95% CI = 0.078–0.466, p = 0.029) and p-tau-217 (β = 0.295, 95% CI = 0.102–0.488, p = 0.027). FA of the central WM was not associated with TES diagnoses. Taken together, these findings suggest that dMRI at the GM/WM boundary could be used to investigate microstructural alterations suggestive of tau pathology-associated neurodegeneration in individuals with TES, the clinical presentation of CTE. Future studies are needed to validate this approach and to identify clinically useful cutoff values for dMRI metrics.

Abstract The brain avidly consumes glucose to fuel neurophysiology. Cancers of the brain, such as glioblastoma (GBM), relinquish physiological integrity and gain the ability to proliferate and invade healthy tissue. How brain cancers rewire glucose utilization to drive aggressive growth remains elusive. Here, we infused 13C-labeled glucose into patients and mice with brain cancer, coupled with quantitative metabolic flux analysis, to map the fates of glucose-derived carbon in tumor vs. cortex. Through the first direct and comprehensive measurements of carbon and nitrogen labeling in both cortex and glioma tissues, we uncover profound metabolic transformations. In human cortex, glucose carbons fuel essential physiologic processes including TCA cycle oxidation and neurotransmitter synthesis. Conversely, gliomas downregulate these processes and scavenge alternative carbon sources such as amino acids from the environment, repurposing glucose-derived carbons to generate molecules needed for proliferation and invasion. Targeting this metabolic rewiring in mice through dietary amino acid modulation selectively alters GBM metabolism, slows tumor growth, and augments the efficacy of standard-of-care treatments. These findings illuminate how aggressive brain tumors exploit glucose to suppress normal physiological activity in favor of malignant expansion and offer potential therapeutic strategies to enhance treatment outcomes.