Exploratory study of using Magnetic resonance Prognostic Imaging markers for Radiotherapy In Cervix cancer (EMPIRIC): a prospective cohort study protocol.

INTRODUCTION: Radical chemoradiotherapy represents the gold standard for locally advanced cervical cancer. However, despite significant progress in improving local tumour control, distant relapse continues to impact overall survival. The development of predictive and prognostic biomarkers is consequently important to risk-stratify patients and identify populations at higher risk of poorer treatment response and survival outcomes. Exploratory study of using Magnetic resonance Prognostic Imaging markers for Radiotherapy In Cervix cancer (EMPIRIC) is a prospective exploratory cohort study, which aims to investigate the role of multiparametric functional MRI (fMRI) using diffusion-weighed imaging (DWI), dynamic contrast-enhanced (DCE) and blood oxygen level-dependent imaging (BOLD) MRI to assess treatment response and predict outcomes in patients undergoing radical chemoradiotherapy for cervical cancer. METHODS AND ANALYSIS: The study aims to recruit 40 patients across a single-centre over 2 years. Patients undergo multiparametric fMRI (DWI, DCE and BOLD-MRI) at three time points: before, during and at the completion of external beam radiotherapy. Tissue and liquid biopsies are collected at diagnosis and post-treatment to identify potential biomarker correlates against fMRI. The primary outcome is to evaluate sensitivity and specificity of quantitative parameters derived from fMRI as predictors of progression-free survival at 2 years following radical chemoradiotherapy for cervical cancer. The secondary outcome is to investigate the roles of fMRI as predictors of overall survival at 2 years and tumour volume reduction across treatment. Statistical analyses using regression models and survival analyses are employed to evaluate the relationships between the derived parameters, treatment response and clinical outcomes. ETHICS AND DISSEMINATION: The EMPIRIC study received ethical approval from the NHS Health Research Authority (HRA) on 14 February 2022 (protocol number RD2021-29). Confidentiality and data protection measures are strictly adhered to throughout the study. The findings of this study will be disseminated through peer-reviewed publications and scientific conferences, aiming to contribute to the growing body of evidence on the use of multiparametric MRI in cervical cancer management. TRIAL REGISTRATION NUMBER: NCT05532930.

Higher interleukin-6 is associated with greater momentary social connection in close relationships in daily life.

Recent evidence has documented associations between higher levels of inflammation and social approach behaviors toward close others in laboratory-based tasks. Yet it is unknown if this translates to interactions with close others in daily life. Given that momentary experiences of social connection have both relational and health consequences, this is a critical gap in our knowledge. To address the association between inflammation and momentary social connection experiences in close relationships, 55 participants provided blood samples on two consecutive days, which were assayed for circulating levels of the inflammatory marker interleukin-6 (IL-6). After providing the first blood sample, participants received the annual influenza vaccine as a mild inflammatory challenge. Participants also reported on cognitive, affective, and behavioral indicators of social connection with a specific close other multiple times across the two study days. Results indicated that levels of IL-6 were positively associated with temporally-proximal indicators of momentary social connection with a close other. Specifically, higher levels of IL-6 were associated with greater feelings of comfort from the close other, greater desire to be near them, and higher reported relationship quality. Greater IL-6 reactivity to the vaccine was only associated with increased reported relationship quality. These data add to the existing literature suggesting that higher levels of IL-6 may motivate social approach toward a close other, extending evidence to now include momentary social connection experiences in daily life.

Delivery of loaded MR1 monomer results in efficient ligand exchange to host MR1 and subsequent MR1T cell activation.

MR1-restricted T cells have been implicated in microbial infections, sterile inflammation, wound healing and cancer. Similar to other antigen presentation molecules, evidence supports multiple, complementary MR1 antigen presentation pathways. To investigate ligand exchange pathways for MR1, we used MR1 monomers and tetramers loaded with 5-(2-oxopropylideneamino)-6-d-ribitylaminouracil (5-OP-RU) to deliver the antigen. Using MR1-deficient cells reconstituted with wild-type MR1 or MR1 molecules that cannot bind 5-OP-RU, we show that presentation of monomer-delivered 5-OP-RU is dependent on cellular MR1 and requires the transfer of ligand from the soluble molecule onto MR1 expressed by the antigen presenting cell. This mode of antigen delivery strengthens the evidence for post-ER ligand exchange pathways for MR1, which could represent an important avenue by which MR1 acquires antigens derived from endocytosed pathogens.

Mouse Memory CD8 T Cell Subsets Defined by Tissue-Resident Memory Integrin Expression Exhibit Distinct Metabolic Profiles.

Tissue-resident memory CD8 T cells (TRM) principally reside in peripheral nonlymphoid tissues, such as lung and skin, and confer protection against a variety of illnesses ranging from infections to cancers. The functions of different memory CD8 T cell subsets have been linked with distinct metabolic pathways and differ from other CD8 T cell subsets. For example, skin-derived memory T cells undergo fatty acid oxidation and oxidative phosphorylation to a greater degree than circulating memory and naive cells. Lung TRMs defined by the cell-surface expression of integrins exist as distinct subsets that differ in gene expression and function. We hypothesize that TRM subsets with different integrin profiles will use unique metabolic programs. To test this, differential expression and pathway analysis were conducted on RNA sequencing datasets from mouse lung TRMs yielding significant differences related to metabolism. Next, metabolic models were constructed, and the predictions were interrogated using functional metabolite uptake assays. The levels of oxidative phosphorylation, mitochondrial mass, and neutral lipids were measured. Furthermore, to investigate the potential relationships to TRM development, T cell differentiation studies were conducted in vitro with varying concentrations of metabolites. These demonstrated that lipid conditions impact T cell survival, and that glucose concentration impacts the expression of canonical TRM marker CD49a, with no effect on central memory-like T cell marker CCR7. In summary, it is demonstrated that mouse resident memory T cell subsets defined by integrin expression in the lung have unique metabolic profiles, and that nutrient abundance can alter differentiation.

Ultra-rapid Electrophilic Cysteine Arylation.

Rapid bond-forming reactions are crucial for efficient bioconjugation. We describe a simple and practical strategy for facilitating ultra-rapid electrophilic cysteine arylation. Using a variety of sulfone-activated pyridinium salts, this uncatalyzed reaction proceeds with exceptionally high rate constants, ranging from 9800 to 320,000 M-1·s-1, in pH 7.0 aqueous buffer at 25 °C. Such reactions allow for stoichiometric bioconjugation of micromolar cysteine within minutes or even seconds. Even though the arylation is extremely fast, the chemistry exhibits excellent selectivity, thus furnishing functionalized peptides and proteins with both high conversion and purity.

Altered Estrous Cyclicity and Feeding Neurocircuitry, but Not Cardiovascular Indices in Female Offspring from Dams with Previous Vertical Sleeve Gastrectomy Surgery.

Metabolic syndrome (MetS), which includes obesity, diabetes, hypertension, hyperlipidemia, and fatty-liver disease, affects more than two-thirds of the U.S. population. Surgical weight loss has been popularized in the last several decades as a means to produce significant weight loss and improvements in the comorbidities of MetS. Women are by far the most common recipients of these surgeries (more than 85%). Women of childbearing age are very likely to pursue surgical weight loss to improve their reproductive function and fertility for childbearing purposes. Significant research using pre-clinical models from our laboratory and clinical data from around the world suggest that surgical weight loss before pregnancy may have negative consequences for offspring. The present study investigates the metabolic endpoints in female-rodent offspring born to dams who had previously received vertical sleeve gastrectomy (VSG) before pregnancy. Comparisons were made to offspring from lean and obese dams. In the adult offspring of either maternal VSG or sham surgery, no differences in body weight, body fat, or lean body mass between groups were identified. The blood pressure measured in a subset of female offspring showed no differences between the VSG and the sham groups. Estrus cyclicity measured by lavage on serial days showed altered cycles in the VSG offspring compared to the controls. For animals that had previously only been exposed to chow, rats were fasted overnight and then given a 1 g meal of either chow or a novel high-fat diet (HFD). The animals were euthanized and paraformaldehyde (PFA)-perfused to perform brain immunohistochemistry for c-Fos, an immediate-early gene activated by novel stimuli. In the VSG rats exposed to either the chow or the HFD meal, the c-Fos-activated cells were significantly blunted in the nucleus of the solitary tract (p < 0.05), the paraventricular nucleus of the hypothalamus (PVN) (p < 0.05), and the dorsal medial nucleus of the hypothalamus (DMH) (p < 0.05) in comparison to the sham controls. These data suggest that the hypothalamic wiring within the brain that controls the response to nutrients and reproductive function was significantly altered in the VSG offspring compared to the offspring of the dams that did not receive weight-loss surgery.

A Shared Pathogenic Mechanism for Valproic Acid and SHROOM3 Knockout in a Brain Organoid Model of Neural Tube Defects.

Neural tube defects (NTDs), including anencephaly and spina bifida, are common major malformations of fetal development resulting from incomplete closure of the neural tube. These conditions lead to either universal death (anencephaly) or severe lifelong complications (spina bifida). Despite hundreds of genetic mouse models of neural tube defect phenotypes, the genetics of human NTDs are poorly understood. Furthermore, pharmaceuticals, such as antiseizure medications, have been found clinically to increase the risk of NTDs when administered during pregnancy. Therefore, a model that recapitulates human neurodevelopment would be of immense benefit to understand the genetics underlying NTDs and identify teratogenic mechanisms. Using our self-organizing single rosette cortical organoid (SOSR-COs) system, we have developed a high-throughput image analysis pipeline for evaluating the SOSR-CO structure for NTD-like phenotypes. Similar to small molecule inhibition of apical constriction, the antiseizure medication valproic acid (VPA), a known cause of NTDs, increases the apical lumen size and apical cell surface area in a dose-responsive manner. GSK3ß and HDAC inhibitors caused similar lumen expansion; however, RNA sequencing suggests VPA does not inhibit GSK3ß at these concentrations. The knockout of SHROOM3, a well-known NTD-related gene, also caused expansion of the lumen, as well as reduced f-actin polarization. The increased lumen sizes were caused by reduced cell apical constriction, suggesting that impingement of this process is a shared mechanism for VPA treatment and SHROOM3-KO, two well-known causes of NTDs. Our system allows the rapid identification of NTD-like phenotypes for both compounds and genetic variants and should prove useful for understanding specific NTD mechanisms and predicting drug teratogenicity.

Architecture of the cortical actomyosin network driving apical constriction in C. elegans.

Apical constriction is a cell shape change that drives key morphogenetic events during development, including gastrulation and neural tube formation. The forces driving apical constriction are primarily generated through the contraction of apicolateral and/or medioapical actomyosin networks. In the Drosophila ventral furrow, the medioapical actomyosin network has a sarcomere-like architecture, with radially polarized actin filaments and centrally enriched non-muscle myosin II and myosin activating kinase. To determine if this is a broadly conserved actin architecture driving apical constriction, we examined actomyosin architecture during C. elegans gastrulation, in which two endodermal precursor cells internalize from the surface of the embryo. Quantification of protein localization showed that neither the non-muscle myosin II NMY-2 nor the myosin-activating kinase MRCK-1 is enriched at the center of the apex. Further, visualization of barbed- and pointed-end capping proteins revealed that actin filaments do not exhibit radial polarization at the apex. Our results demonstrate that C. elegans endodermal precursor cells apically constrict using a mixed-polarity actin filament network and with myosin and a myosin activator distributed throughout the network. Taken together with observations made in other organisms, our results demonstrate that diverse actomyosin architectures are used in animal cells to accomplish apical constriction.

Social determinants of cognitive outcomes in survivors of pediatric brain tumors treated with conformal radiation therapy.

BACKGROUND: Social determinants of health including parental occupation, household income, and neighborhood environment are predictors of cognitive outcomes among healthy and ill children; however, few pediatric oncology studies have investigated this relationship. This study utilized the Economic Hardship Index (EHI) to measure neighborhood-level social and economic conditions to predict cognitive outcomes among children treated for brain tumors (BT) with conformal radiation therapy (RT). METHODS: Two hundred and forty-one children treated on a prospective, longitudinal, phase II trial of conformal photon RT (54-59.4 Gy) for ependymoma, low-grade glioma, or craniopharyngioma (52% female, 79% white, age at RT = 7.76 ±â€…4.98 years) completed serial cognitive assessments (intelligence quotient [IQ], reading, math, and adaptive functioning) for ten years. Six US census tract-level EHI scores were calculated for an overall EHI score: unemployment, dependency, education, income, crowded housing, and poverty. Established socioeconomic status (SES) measures from the extant literature were also derived. RESULTS: Correlations and non-parametric tests revealed EHI variables share modest variance with other SES measures. Income, unemployment, and poverty overlapped most with individual SES measures. Linear mixed models, accounting for sex, age at RT, and tumor location, revealed EHI variables predicted all cognitive variables at baseline and change in IQ and math over time, with EHI overall and poverty most consistent predictors. Higher economic hardship was associated with lower cognitive scores. CONCLUSIONS: Neighborhood-level measures of socioeconomic conditions can help inform understanding of long-term cognitive and academic outcomes in survivors of pediatric BT. Future investigation of poverty's driving forces and the impact of economic hardship on children with other catastrophic diseases is needed.

Testing of a Novel Method for Securing Ligaments Against Bone During Simultaneous Medial and Lateral Elbow Ligament Reconstruction.

PURPOSE: A ligament reconstruction method that simultaneously tensions the medial and lateral sides of the elbow and maintains tension with compression plates on the proximal ulna is proposed for the treatment of bidirectional elbow ligament instability. Graft slippage, catastrophic failure, and excessive displacement were evaluated. Biomechanical stability without graft slippage was hypothesized. METHODS: Eight cadaveric ligament reconstruction simulations were created through the dissection of three cadaver arms. Each reconstruction was statically tested with 160 N in a manner where it was first augmented with an absorbable suture and then without. Then, 3 more ligament reconstruction simulations were created for dynamic testing with each undergoing testing at 80 N for 2,000 cycles at 2 Hz. Construct displacement and graft slippage were recorded for each load application. RESULTS: No grafts failed catastrophically and no graft slippage was observed with either static or dynamic loading. Under static loading, the mean change in displacement between augmented and nonaugmented ligament reconstruction simulations was 28.7% ± 21% (augmented 3.95 ± 1.81 mm vs nonaugmented 4.89 ± 2.22 mm). The mean stiffness was 66.6 ± 26.6 N/mm for augmented and 64.6 ± 23.2 N/mm for nonaugmented simulations. With dynamic loading, the mean displacement for augmented graft ligament reconstruction simulations was 1.55 ± 0.16 mm compared with 2.18 ± 0.77 mm for nonaugmented reconstruction simulations. CONCLUSIONS: This method of fixation to the proximal ulna for the simultaneous reconstruction of medial and lateral elbow ligaments successfully prevented graft slippage without excessive construct displacement during static and dynamic testing. Ligament augmentation with absorbable sutures decreased the construct displacement. CLINICAL RELEVANCE: This ligament fixation method may be a viable alternative for the treatment of concomitant medial and lateral elbow instability.

Financial Implications of Enhanced Recovery After Surgery Protocols in Microsurgical Breast Reconstruction.

INTRODUCTION: Surgical advancements in breast reconstruction have allowed a shift toward optimizing patient-reported outcomes and efficiency measures. The enhanced recovery after surgery (ERAS) protocol has been instrumental in improving outcomes, but the effect of these protocols on health care spending has not been examined. This study aims to assess the effect of ERAS protocols on the length of hospital stay and costs associated with microsurgical breast reconstruction. METHODS: In 2018, the authors implemented an ERAS protocol for patients undergoing microsurgical breast reconstruction that included perioperative procedures involving patient education and care. Subjects included patients who underwent deep inferior epigastric perforator flap breast reconstruction at the authors' institution between 2016 and 2019. Data were gathered from the electronic medical record and the hospital system's finance department, and patients were divided into pre-ERAS and ERAS cohorts. A 2-sample t test was used for statistical analysis. RESULTS: The study included 269 patients with no statistically significant differences in demographic data between the cohorts. The average length of hospitalization was 3.46 days for the pre-ERAS group and 2.45 days for the ERAS group ( P = 0.000). In a linear regression, the ERAS protocol predicted a 1.04-day decrease in the length of stay ( P = 0.000). Overall, total direct cost decreased by 7.5% with the ERAS protocol. CONCLUSION: The rising cost of health care presents a challenge for providers to reduce the cost burden placed on our health system while providing the highest-quality care. This study demonstrates that the use of standardized ERAS protocols can achieve this 2-fold goal.

Chronic Obstructive Pulmonary Disease and Cigarette Smoke Lead to Dysregulated Mucosal-associated Invariant T-Cell Activation.

Chronic obstructive pulmonary disease (COPD) is associated with airway inflammation, increased infiltration by CD8+ T lymphocytes, and infection-driven exacerbations. Although cigarette smoke is the leading risk factor for COPD, the mechanisms driving the development of COPD in only a subset of smokers are incompletely understood. Lung-resident mucosal-associated invariant T (MAIT) cells play a role in microbial infections and inflammatory diseases. The role of MAIT cells in COPD pathology is unknown. Here, we examined MAIT cell activation in response to cigarette smoke-exposed primary human bronchial epithelial cells (BECs) from healthy, COPD, or smoker donors. We observed significantly higher baseline MAIT cell responses to COPD BECs than healthy BECs. However, infected COPD BECs stimulated a smaller fold increase in MAIT cell response despite increased microbial infection. For all donor groups, cigarette smoke-exposed BECs elicited reduced MAIT cell responses; conversely, cigarette smoke exposure increased ligand-mediated MR1 surface translocation in healthy and COPD BECs. Our data demonstrate that MAIT cell activation is dysregulated in the context of cigarette smoke and COPD. MAIT cells could contribute to cigarette smoke- and COPD-associated inflammation through inappropriate activation and reduced early recognition of bacterial infection, contributing to microbial persistence and COPD exacerbations.

Milnacipran Ameliorates Executive Function Impairments following Frontal Lobe Traumatic Brain Injury in Male Rats: A Multimodal Behavioral Assessment.

Traumatic brain injuries (TBIs) affect more than 10 million patients annually worldwide, causing long-term cognitive and psychosocial impairments. Frontal lobe TBIs commonly impair executive function, but laboratory models typically focus primarily on spatial learning and declarative memory. We implemented a multi-modal approach for clinically relevant cognitive-behavioral assessments of frontal lobe function in rats with TBI and assessed treatment benefits of the serotonin-norepinephrine reuptake inhibitor, milnacipran (MLN). Two attentional set-shifting tasks (AST) evaluated cognitive flexibility via the rats' ability to locate food-based rewards by learning, unlearning, and relearning sequential rule sets with shifting salient cues. Adult male rats reached stable pre-injury operant AST (oAST) performance in 3-4 weeks, then were isoflurane-anesthetized, subjected to a unilateral frontal lobe controlled cortical impact (2.4 mm depth, 4 m/sec velocity) or Sham injury, and randomized to treatment conditions. Milnacipran (30 mg/kg/day) or vehicle (VEH; 10% ethanol in saline) was administered intraperitoneally via implanted osmotic minipumps (continuous infusions post-surgery, 60 µL/h). Rats had a 10-day recovery post-TBI/Sham before performing light/location-based oAST for 10 days and, subsequently, odor/media-based digging AST (dAST) on the last test day (26-27 days post-injury) before sacrifice. Both AST tests revealed significant deficits in TBI+VEH rats, seen as elevated total trials and errors (p < 0.05), which generally normalized in MLN-treated rats (p < 0.05). This first simultaneous dual AST assessment demonstrates oAST and dAST are sufficiently sensitive and robust to detect subtle attentional and cognitive flexibility executive impairments after frontal lobe TBI in rats. Chronic MLN administration shows promise for attenuation of post-TBI executive function deficits, thus meriting further investigation.

Testing of Novel Total Elbow Prostheses Using Active Motion Experimental Setup.

PURPOSE: The goal of this study was to test a novel uncemented and unconstrained total elbow arthroplasty (Kaufmann total elbow) design that is stabilized through a ligament reconstruction. METHODS: We quantified the implant stability after 25,000 cycles, which represents the time between implantation and when ligament and bone healing has occurred. We used an active motion experimental setup that applies tendon loads via pneumatic cylinders and reproduces the forearm-originating dynamic stabilizers of the elbow. The novel total elbow arthroplasty was actuated for 5,000 full flexion-extension cycles at 5 different shoulder positions. Four Sawbones and 4 cadaver elbows were employed. Angular laxity and implant stability were recorded prior to testing and after each 5,000-loading cycle. RESULTS: Four Sawbones and 4 cadaver elbows were implanted with the uncemented total elbow arthroplasty and did not demonstrate fixation failure or substantial laxity after 25,000 cycles of loading imparted at different shoulder positions. CONCLUSIONS: Our findings demonstrate that the Kaufmann total elbow replacement implanted into cadaver and Sawbones specimens did not exhibit fixation failure or excessive laxity after 25,000 cycles. CLINICAL RELEVANCE: An uncemented, nonmechanically linked total elbow arthroplasty that gains component fixation using intramedullary screws and employs a ligament reconstruction to stabilize the elbow has the potential to be a valuable management option, particularly in younger patients.

Genome-wide CRISPRi Screen in Human iNeurons to Identify Novel Focal Cortical Dysplasia Genes.

Focal cortical dysplasia (FCD) is a common cause of focal epilepsy that typically results from brain mosaic mutations in the mTOR cell signaling pathway. To identify new FCD genes, we developed an in vitro CRISPRi screen in human neurons and used FACS enrichment based on the FCD biomarker, phosphorylated S6 ribosomal protein (pS6). Using whole-genome (110,000 gRNAs) and candidate (129 gRNAs) libraries, we discovered 12 new genes that significantly increase pS6 levels. Interestingly, positive hits were enriched for brain-specific genes, highlighting the effectiveness of using human iPSC-derived induced neurons (iNeurons) in our screen. We investigated the signaling pathways of six candidate genes: LRRC4, EIF3A, TSN, HIP1, PIK3R3, and URI1. All six genes increased phosphorylation of S6. However, only two genes, PIK3R3 and HIP1, caused hyperphosphorylation more proximally in the AKT/mTOR/S6 signaling pathway. Importantly, these two genes have recently been found independently to be mutated in resected brain tissue from FCD patients, supporting the predictive validity of our screen. Knocking down each of the other four genes (LRRC4, EIF3A, TSN, and URI1) in iNeurons caused them to become resistant to the loss of growth factor signaling; without growth factor stimulation, pS6 levels were comparable to growth factor stimulated controls. Our data markedly expand the set of genes that are likely to regulate mTOR pathway signaling in neurons and provide additional targets for identifying somatic gene variants that cause FCD.

Reirradiation Options for Previously Irradiated Prostate cancer (RO-PIP): Feasibility study investigating toxicity outcomes following reirradiation with stereotactic body radiotherapy (SBRT) versus high-dose-rate brachytherapy (HDR-BT).

INTRODUCTION: Radiotherapy is the most common curative treatment for non-metastatic prostate cancer; however, up to 13% of patients will develop local recurrence within 10 years. Patients can undergo further and potentially curative treatment including salvage surgery, brachytherapy (BT), external beam radiotherapy, high-intensity focused ultrasound and cryotherapy. Systematic review shows that high-dose-rate (HDR) BT and stereotactic body radiotherapy (SBRT) have the best outcomes in terms of biochemical control and lowest side effects. The reirradiation options for previously irradiated prostate cancer (RO-PIP) trial aims to determine the feasibility of recruitment to a trial randomising patients to salvage HDR-BT or SBRT and provide prospective data on patient recorded toxicity outcomes that will inform a future phase III trial. METHODS AND ANALYSIS: The primary endpoint of the RO-PIP feasibility study is to evaluate the patient recruitment potential over 2 years to a trial randomising to either SBRT or HDR-BT for patients who develop local recurrence of prostate cancer following previous radiation therapy. The aim is to recruit 60 patients across 3 sites over 2 years and randomise 1:1 to SBRT or HDR-BT. Secondary objectives include recording clinician and patient-reported outcome measures to evaluate treatment-related toxicity. In addition, the study aims to identify potential imaging, genomic and proteomic biomarkers that are predictive of toxicity and outcome based on hypoxia status, a prognostic marker of prostate cancer. ETHICS AND DISSEMINATION: This study has been approved by the Yorkshire and The Humber-Bradford Leeds Research Ethics Committee (Reference: 21/YH/0305, IRAS: 297060, January 2022). The results will be presented in national and international conferences, published in peer-reviewed journals and will be communicated to relevant stakeholders. A plain English report will be shared with the study participants, patients' organisations and media. TRIAL REGISTRATION NUMBER: ISRCTN 12238218 (Amy Ackroyd NIHR CPMS Team).

Trends in endpoint use in pivotal trials and efficacy for US Food and Drug Administration-approved solid tumor therapies, 1995-2021.

BACKGROUND: Many cancer therapies are now approved based on surrogate endpoints such as progression-free survival (PFS) to ensure that patients have speedy access to life-saving cancer medicines. However, the link between surrogate endpoints and overall survival (OS) is not well established in many cancers. OBJECTIVE: To characterize trends in endpoints used in pivotal trials leading to approval for US Food and Drug Administration (FDA)-approved solid tumor therapies and their efficacy from 1995 to 2021. METHODS: We reviewed the FDA Oncology (Cancer)/Hematologic Malignancies Approval Notifications webpage to extract data on median OS and PFS among solid tumor therapy approvals from 1995 to 2021. We summarized trends in percentage of trials reporting OS vs PFS, median OS and PFS, and trial designs. We conducted subgroup analyses for lung and breast cancer therapies. RESULTS: Median OS was reported more frequently until 2010 to 2012, when median PFS and OS were reported in 65.2% and 60.9% of trials, respectively. Between 1995 and 2021, there were no observable trends in median OS over time for solid tumor therapy approvals. Median PFS increased by 3.0 months over time. For lung cancer therapies, median OS increased by 6.8 months between the time periods of 1998-2000 and 2019-2021, whereas median PFS increased by 5.0 months between the time periods of 2007-2009 and 2019-2021. For breast cancer therapy, median OS slightly decreased over time, whereas median PFS has increased by 3.4 months since 1995. There has been a recent shift in use of single-arm trials leading to oncology drug approvals. CONCLUSIONS: There has been a transition from reporting OS to PFS, and median PFS has increased by 3 months while median OS has remained stable. The different trends in overall and progression-free survival highlights the challenge and importance of measuring the value of oncology drugs. DISCLOSURES: Dr Suh reports personal fees from Bayer US LLC.

Localization of macrophage subtypes and neutrophils in the prostate tumor microenvironment and their association with prostate cancer racial disparities.

BACKGROUND: Black men are two to three times more likely to die from prostate cancer (PCa) than White men. This disparity is due in part to discrepancies in socioeconomic status and access to quality care. Studies also suggest that differences in the prevalence of innate immune cells and heightened function in the tumor microenvironment of Black men may promote PCa aggressiveness. METHODS: We evaluated the spatial localization of and quantified CD66ce+ neutrophils by immunohistochemistry and CD68+ (pan), CD80+ (M1), and CD163+ (M2) macrophages by RNA in situ hybridization on formalin-fixed paraffin-embedded tissues from organ donor "normal" prostate (n = 9) and radical prostatectomy (n = 38) tissues from Black and White men. Neutrophils were quantified in PCa and matched benign tissues in tissue microarray (TMA) sets comprised of 560 White and 371 Black men. Likewise, macrophages were quantified in TMA sets comprised of tissues from 60 White and 120 Black men. The phosphatase and tensin homolog (PTEN) and ETS transcription factor ERG (ERG) expression status of each TMA PCa case was assessed via immunohistochemistry. Finally, neutrophils and macrophage subsets were assessed in a TMA set comprised of distant metastatic PCa tissues collected at autopsy (n = 6) sampled across multiple sites. RESULTS: CD66ce+ neutrophils were minimal in normal prostates, but were increased in PCa compared to benign tissues, in low grade compared to higher grade PCa, in PCa tissues from White compared to Black men, and in PCa with PTEN loss or ERG positivity. CD163+ macrophages were the predominant macrophage subset in normal organ donor prostate tissues from both Black and White men and were significantly more abundant in organ donor compared to prostatectomy PCa tissues. CD68,+  CD80,+ and CD163+ macrophages were significantly increased in cancer compared to benign tissues and in cancers with ERG positivity. CD68+ and CD163+ macrophages were increased in higher grade cancers compared to low grade cancer and CD80 expression was significantly higher in benign prostatectomy tissues from Black compared to White men. CONCLUSIONS: Innate immune cell infiltration is increased in the prostate tumor microenvironment of both Black and White men, however the composition of innate immune cell infiltration may vary between races.

Augmenting Osteochondral Autograft Transplantation and Bone Marrow Aspirate Concentrate with Particulate Cartilage Extracellular Matrix Is Associated With Improved Outcomes.

BACKGROUND: Osteochondral autograft transplant (OAT) is often used to treat large osteochondral lesions of the talus and is generally associated with good outcomes. The addition of adjuncts such as cartilage extracellular matrix with bone marrow aspirate concentrate (ECM-BMAC) may further improve the OAT procedure but have not been thoroughly studied. We hypothesized that the placement of ECM-BMAC around the OAT graft would improve radiographic and patient-reported outcomes following OAT. METHODS: Patients who received OAT, with ECM-BMAC or BMAC alone, were screened and their charts were reviewed. For patients who did receive ECM-BMAC, the mixture was spread around the edges of the OAT plug and into any surrounding areas of cartilage damage. Survey and radiographic data were collected. Average follow-up in both groups was over 2 years. Magnetic resonance imaging scans were scored using the Magnetic Resonance Observation of Cartilage Tissue (MOCART) system. Outcomes were compared statistically between groups. RESULTS: Patients treated with ECM-BMAC (n = 34) demonstrated significantly greater improvement of scores in the FAOS categories Symptoms (17 vs -3; P = .02) and Sports Activities (40 vs 7; P = .02), and the MOCART category Subchondral Lamina (P = .008) compared to those treated with BMAC alone (n = 30). They also experienced significantly lower rates of postoperative cysts (53% vs 18%, P = .04) and edema (94% vs 59%, P = .02). CONCLUSION: The addition of ECM-BMAC to OAT was associated with improved imaging and clinical outcomes compared to OAT with BMAC alone.