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Evidence from the Phase III PACIFIC trial established durvalumab, a monoclonal antibody (mAb) targeting PD-L1, following concurrent chemoradiotherapy (cCRT) as a global standard of care for patients with unresectable, stage III non-small-cell lung cancer (NSCLC). There remains an unmet need to improve upon the outcomes achieved with the PACIFIC regimen. Combining durvalumab with other immunotherapies may improve outcomes further. Two such immunotherapies include oleclumab, an mAb targeting CD73, and monalizumab, an mAb targeting NKG2A. Both agents demonstrated antitumor activity in early-phase trials. PACIFIC-9 (NCT05221840) is an international, double-blind, randomized, placebo-controlled, Phase III trial comparing durvalumab plus either oleclumab or monalizumab with durvalumab plus placebo in patients with unresectable, stage III NSCLC and no disease progression following cCRT. Clinical Trial Registration: NCT05221840 (ClinicalTrials.gov) Plain Language Summary Durvalumab is a treatment that helps the body's immune system to identify and attack cancer cells by binding to a protein called PD-L1. Studies show that durvalumab lowers the risk of cancer growing or spreading, and prolongs survival, when administered after chemotherapy and radiation therapy ('chemoradiotherapy') in patients with a type of lung cancer called stage III non-small-cell lung cancer (NSCLC) for whom surgery is not an option. Two antibody treatments have been developed that may help a patient's immune system to identify and attack cancer cells. Oleclumab binds to a protein on cancer cells called CD73, which prevents the production of adenosine, a chemical that obstructs the immune system from attacking the cancer. Monalizumab binds to NKG2A, a protein on immune cells that inhibits their ability to destroy cancer cells. Early studies suggest that combining either of these treatments with durvalumab may be better than durvalumab alone for slowing the growth and spread of cancer in patients with NSCLC. PACIFIC-9 is a study that aims to recruit approximately 999 patients with stage III NSCLC for whom surgery is not an option and who have completed chemoradiotherapy without the cancer growing or spreading. Patients will be randomly assigned in equal numbers to receive up to a year of treatment with durvalumab plus oleclumab, durvalumab plus monalizumab or durvalumab plus placebo. The primary measure of efficacy is the length of time that patients remain alive without the cancer growing or spreading for each combination versus durvalumab plus placebo. Executive summary The PACIFIC regimen Durvalumab is a monoclonal antibody that binds to PD-L1 and overcomes PD-L1 mediated inhibition of T-cell activation, allowing T cells to recognize and kill tumor cells. The Phase III placebo-controlled, PACIFIC trial (NCT02125461) demonstrated significant improvements in progression-free survival (PFS) and overall survival with durvalumab in patients with unresectable, stage III non-small-cell lung cancer (NSCLC) whose disease had not progressed following platinum-based, concurrent chemoradiotherapy (cCRT); the PACIFIC regimen is now a global standard of care in this population. Oleclumab & monalizumab Extracellular adenosine can act as an immunosuppressant within the tumor microenvironment; oleclumab is a monoclonal antibody that binds to and blocks CD73, an enzyme on the surface of tumor cells that drives the production of extracellular adenosine. NKG2A is a receptor on T cells and natural killer (NK) cells that can inhibit T cell and NK cell effector function when it binds to HLA-E; monalizumab is a monoclonal antibody that binds to NKG2A, preventing it from inhibiting NK and T cell function. In the open-label, randomized, Phase II COAST trial (NCT03822351) the combination of durvalumab with oleclumab, and durvalumab with monalizumab, were both associated with encouraging clinical activity compared with durvalumab alone in patients with unresectable, stage III NSCLC and no progression after cCRT; the findings of COAST support further evaluation of these combinations in a Phase III trial. PACIFIC-9 PACIFIC-9 (NCT05221840) is an international, double-blind, randomized, placebo-controlled, Phase III trial comparing the efficacy and safety of durvalumab plus oleclumab and durvalumab plus monalizumab versus durvalumab plus placebo in patients with unresectable, stage III NSCLC. The trial is enrolling men and women aged 18 years or older with histologically or cytologically documented, unresectable, stage III NSCLC according to the TNM system as described in the International Association for the Study of Lung Cancer staging manual (8th edition), whose disease has not progressed following definitive, platinum-based cCRT. The primary end point is PFS, defined as time from randomization until progression per Response Evaluation Criteria in Solid Tumors version 1.1 as assessed by blinded independent central review, or death due to any cause. [ABSTRACT FROM AUTHOR]

Early diagnosis of post‐traumatic osteoarthritis (PTOA) is critical for designing better treatments before the degradation becomes irreversible. We utilized multimodal high‐resolution imaging to investigate early‐stage deterioration in articular cartilage and the subchondral bone plate from a sub‐critical impact to the knee joint, which initiates PTOA. The knee joints of 12 adult rabbits were mechanically impacted once on the femoral articular surface to initiate deterioration. At 2‐ and 14‐week post‐impact surgery, cartilage‐bone blocks were harvested from the impact region in the animals (N = 6 each). These blocks were assessed for deterioration using polarized light microscopy (PLM), microcomputed tomography (μCT), and biochemical analysis. Statistically significant changes were noted in the impact tissues across the calcified zone (CZ) at 14 weeks post‐impact: the optical retardation values in the CZ of impact cartilage had a drop of 29.0% at 14 weeks, while the calcium concentration in the CZ of impact cartilage also had a significant drop at 14 weeks. A significant reduction of 6.3% in bone mineral density (BMD) was noted in the subchondral bone plate of the impact samples at 14 weeks. At 2 weeks post‐impact, only minor, non‐significant changes were measured. Furthermore, the impact knees after 14 weeks had greater structural changes compared with the 2‐week impact knees, indicating progressive degradation over time. The findings of this study facilitated a connection between mineralization alterations and the early deterioration of knee cartilage after a mechanical injury. In a broader context, these findings can be beneficial in improving clinical strategies to manage joint injuries. [ABSTRACT FROM AUTHOR]

Radiation therapy (RT) activates multiple immunologic effects in the tumor microenvironment (TME), with diverse dose-response relationships observed. We hypothesized that, in contrast with homogeneous RT, a heterogeneous RT dose would simultaneously optimize activation of multiple immunogenic effects in a single TME, resulting in a more effective antitumor immune response. Using high-dose-rate brachytherapy, we treated mice bearing syngeneic tumors with a single fraction of heterogeneous RT at a dose ranging from 2 to 30 gray. When combined with dual immune checkpoint inhibition in murine models, heterogeneous RT generated more potent antitumor responses in distant, nonirradiated tumors compared with any homogeneous dose. The antitumor effect after heterogeneous RT required CD4 and CD8 T cells and low-dose RT to a portion of the tumor. At the 3-day post-RT time point, dose heterogeneity imprinted the targeted TME with spatial differences in immune-related gene expression, antigen presentation, and susceptibility of tumor cells to immune-mediated destruction. At a later 10-day post-RT time point, high-, moderate-, or low-RT-dose regions demonstrated distinct infiltrating immune cell populations. This was associated with an increase in the expression of effector-associated cytokines in circulating CD8 T cells. Consistent with enhanced adaptive immune priming, heterogeneous RT promoted clonal expansion of effector CD8 T cells. These findings illuminate the breadth of dose-dependent effects of RT on the TME and the capacity of heterogeneous RT to promote antitumor immunity when combined with immune checkpoint inhibitors. Editor's summary: Radiation therapy (RT) is usually administered as a single dose across a tumor. However, not all radiation doses are created equal. High radiation doses promote immunogenic cell death, medium radiation doses promote type I interferon responses, and low radiation doses promote inflammatory cytokine production and immune cell trafficking. To reap the benefits of all three doses, Jagodinsky et al. treated murine tumors with heterogeneous RT, where different regions of the tumor were treated with different RT doses. The authors found that this heterogeneous approach outperformed homogeneous dose RT in a T cell–dependent manner and could be combined with immune checkpoint inhibition. These data support further clinical development of heterogeneous RT. —Courtney Malo [ABSTRACT FROM AUTHOR]

This study examined the effects of plyometric-based structured game active breaks on fundamental movement skills (FMS), muscular fitness, student self-perception, and teacher's rating of actual behaviour in Grade 3 and 4 students. Primary school children aged 8-10 years old, from four classes, were cluster-randomly assigned to an intervention group (IG) (n = 54) or a control group (CG) (n = 48). The IG participated in structured plyometric-based game active breaks for 7-10 minutes daily, for six consecutive weeks. The CG resumed their regular daily school routine. FMS were assessed with the Canadian Agility Movement Skills Assessment test, and muscular fitness with the standing long jump (SLJ), countermovement jump (CMJ), and seated medicine ball chest throw tests. The Self-Perception Profile for Children and the Teacher's Rating Scale of Child's Actual Behaviour assessed student self-perception and teacher's perception of student actual behaviour, respectively. A significant (p < 0.01) interaction group by time was observed, with greater improvements in the IG compared to the CG in FMS (%diff = 13.11, ηp² = 0.12), SLJ (%diff = 6.67, ηp² = 0.02), seated medicine ball chest throw (%diff = 4.69, ηp² = 0.08), student social self-perception (%diff = 9.31, ηp² = 0.10), student scholastic selfperception (%diff = 7.27, ηp² = 0.10), and teacher perception of student social competence (%diff = 8.31, ηp² = 0.05). No difference ( p > 0.05) was found in other variables. Integrating plyometric-based structured game active breaks into primary school settings evidenced improvement in FMS, muscular fitness, student selfperception, and teacher's rating of student actual behaviour. [ABSTRACT FROM AUTHOR]

Traumatized knee greatly contributes to osteoarthritis (OA) of the knee in young adults. To intervene effectively before the onset of severe structural disruption, detection of the disease at the early onset is crucial. In this study, we put together the findings for the detection of OA from the femoral knee joint cartilage of the rabbit at 6 weeks posttrauma. Articular cartilage samples are taken from the impacted and nonimpacted joints at 0 week (serving as the control group) and at 6 weeks posttrauma by minimal force. The samples were imaged using microscopic magnetic resonance imaging (µMRI) at 11.7 µm/pixel and polarized light microscopy (PLM) at 1 µm/pixel. In addition, an inductively coupled plasma ‐ optical emission spectrometry analysis was performed using the adjacent cartilage samples. The outcomes of this study demonstrate an increase in T2 values in 6 weeks samples compared to the 0 week samples by µMRI technique, indicating a general increase of tissue hydration within cartilage. PLM detects a decrease in the average thickness of the superficial zones in the posttraumatic osteoarthritis samples, significant in the impacted femurs. There was an average increasing trend of maximum retardation in the tide mark in comparison to the reported calcium concentration (mg/L) in impacted samples suggesting a possible rise in mineralization in the 6 weeks samples. Qualitatively, physical observation of the joint after 6 weeks showed signs of reddening in the anterior femur suggesting the disease process is a localized phenomenon. Through microscopic imaging, we are able to detect these changes at 6 weeks posttrauma qualitatively and quantitatively. [ABSTRACT FROM AUTHOR]