Citations

Abstract Intravital microscopy enables dynamic and real‐time visualisation of microscopic structures in living tissues without the need for fixation, with real‐life applicability being illustrated by several first‐in‐human studies in different cancers. Its use in preclinical models has yielded important observations of the microvasculature of both healthy and diseased tissues. It has further enabled the observation of the interactions between important components of the tissue microenvironment such as immune cells and neighbouring microvessels. Important recent technological advances, however, have enabled the translation of this technology to human use. Here, we review the main advances in intravital microscopy and some of the most recent uses in different human disease settings.

BACKGROUND AND OBJECTIVES: The therapeutic approach for small- and medium-sized vestibular schwannoma (VS) with normal hearing function remains controversial, with limited comparative data regarding hearing outcomes after stereotactic radiosurgery (SRS) or observation (OBS). We evaluated the serviceable hearing preservation, loss of American Academy of Otolaryngology-Head and Neck Surgery class A hearing, and tumor control (TC) across individuals with Koos grade I and II VSs and normal hearing at presentation who underwent SRS or OBS. METHODS: In this multicenter international study, we retrospectively analyzed the hearing, radiological, and neurological outcomes of patients who underwent SRS (SRS group) or OBS (OBS group). The cohorts were matched using propensity scores based on age, sex, tumor volume, pure-tone average, and speech discrimination score at a 1:1 ratio without replacement. RESULTS: After matching, each group comprised 57 patients. The median follow-up was 49 and 37 months for the SRS and the OBS groups, respectively ( P = .3). The 5- and 9-year serviceable hearing preservation rates in the SRS group were 76.2% and 42.4% vs 56.1% and 16.8% in the OBS group ( P = .17). Class A preservation occurred in 57.9% (33/57) of the SRS and 52.6% (30/57) of the OBS cohorts ( P = .70). Regarding the TC rates, SRS was associated with significantly higher TC rates ( P < .0001). CONCLUSION: We found that SRS is significantly superior regarding TC and provided noninferior hearing outcomes compared with OBS in VS patients with American Academy of Otolaryngology-Head and Neck Surgery class A hearing at presentation. Therefore, we suggest performing SRS in individuals with VS and normal hearing function.

Background: Pneumocystis jirovecii pneumonia (PJP) is life-threatening for immunocompromised patients. No consensus exists on PJP prophylaxis for immunosuppressed patients without HIV, transplant, or cancer. Methods: We retrospectively reviewed the electronic health records of adult immunosuppressed patients with PJP diagnosed between 1990 and 2020 at Mayo Clinic. Patients with HIV, solid organ transplants, or cancer were excluded. Demographic data, treatments, and outcomes were manually abstracted. Results: The most common indications for immunosuppression were rheumatoid arthritis (19.7%), vasculitis (18.1%), and interstitial lung disease (ILD) not related to connective tissue disease (17.6%). Despite having high risk of PJP, 86.0% of patients did not receive PJP prophylaxis. Corticosteroids were the most common immunosuppressive agent used (84.5%), with 64.4% of patients receiving high-dose treatment. Nonbiologic disease-modifying antirheumatic drugs were used for 49.7%, including methotrexate (51.0%), azathioprine (22.9%), and hydroxychloroquine (11.5%). Biologics were prescribed for 25.4%, primarily rituximab (59.2%) and infliximab (22.4%). Hospitalization occurred for 76.7% of patients; 70.3% required intensive care unit (ICU) admission, and 46.6% received mechanical ventilation. The in-hospital mortality rate was 30.4% overall and 53.6% for patients on ventilation. Predictors of death included ILD [odds ratio (OR), 4.61; 95% CI, 1.75-13.00], ICU admission (OR, 3.60; 95% CI, 1.19-11.08), and ventilator use (OR, 3.46; 95% CI, 1.30-9.79). Biologic use was associated with lower odds of death (OR, 0.34; 95% CI, 0.11-0.89). Conclusions: Most patients in our cohort did not receive PJP prophylaxis, and outcomes were poor with high mortality rates. Standardized risk stratification and prophylaxis protocols are needed to improve outcomes.

OBJECTIVE The evidence on ankylosing spinal disorders (ASDs), including ankylosing spondylitis (AS) and diffuse idiopathic skeletal hyperostosis (DISH), in the context of spinal fracture stems from studies with relatively small sample sizes. There are no studies addressing the patient-reported outcome measures (PROMs) and health-related quality of life (HRQOL) outcomes associated with spinal fracture in this population. The aim of this study was to investigate differences in complications, mortality, PROMs, and HRQOL in patients with and without ASD who had been treated for spinal fracture. METHODS This is a nationwide multicenter retrospective study of prospectively collected data from the Swedish Fracture Register. All patients with fractures of the cervical, thoracic, or lumbar spine treated surgically and conservatively between January 2015 and December 2021 were eligible for inclusion. Two groups of patients were formed based on the presence or absence of concomitant ASD. Primary outcomes of interest included death and PROMs. For surgically treated patients, data on complications and reoperation rates were retrieved. Propensity score matching with a ratio of 1:1 was used to balance the groups prior to intergroup comparison. Variables included in the matching process were age, sex, mechanism of injury, neurological function on admission (Frankel grade), injury type (high vs low energy), fracture type, injured spinal level, time to treatment, and type of treatment (surgical vs conservative). Kaplan-Meier analyses were used to study overall survival following injury. RESULTS A total of 14,604 patients without ASD and 1368 patients with ASD were included in this study. High-energy injuries were less frequent in patients with ASD (13% vs 24%, p < 0.001). Moreover, patients with ASD were less likely to be neurologically intact on admission (90% vs 94%, p < 0.001). There were 1707 surgically treated patients without ASD and 559 with the disorder. After matching, a higher overall risk of reoperation was found among patients with ASD (9.1% vs 3.4%, p = 0.007). Surgical site infections requiring reoperation (p = 0.012), but not construct failure or CSF leakage requiring reoperation (p ≥ 0.05), were more common among the patients with ASD. Postmatching, there were no differences in overall survival between ASD and non-ASD cases (p > 0.05). Moreover, patients with and without ASD had similar PROMs, as indicated by the EQ-5D-3L index at 1 year after injury (p = 0.59). CONCLUSIONS Self-reported recovery 1 year after spinal fracture occurred to a similar extent in patients with and without ASD. Moreover, ASD alone was not a significant risk factor for death. Finally, surgically treated patients with ASD experienced higher rates of postoperative complications and reoperations following surgery.

OBJECTIVE The landscape of healthcare policies has undergone significant reforms, with a notable shift toward a patient-centered basis. This change has prioritized the use of metrics reflecting subjective patient-reported outcome measures (PROMs). However, these metrics are often limited, especially in terms of determining clinically relevant changes over time. The concept of the minimal clinically important difference (MCID) has been introduced to address this limitation. In this study, the authors aimed to assess the predictive capability of relative change and its corresponding threshold value, the minimal clinically important relative change (MCIRC), as an alternative to the absolute difference and MCID. METHODS Prospectively collected data from 2006 to 2021 were obtained from the Swedish Spine Registry (Swespine). PROMs included the numeric rating scale (NRS) neck and arm pain scores, the EQ-5D index and EQ visual analog scale (VAS), and the Neck Disability Index (NDI). Anchor-based methods were used to determine MCID and MCIRC. Absolute differences and relative changes were compared in terms of predictive power using the area under the receiver operating characteristic curve (AUC). RESULTS A total of 5323 patients were included. The chosen MCID values were −3 for NRS neck pain, −3 for NRS arm pain, 0.08 for EQ-5D index, 13 for EQ VAS, and −30 for NDI scores. The chosen MCIRC values were −40% for NRS neck pain, −50% for arm pain, 323% for EQ-5D index, 55% for EQ VAS, and −33% for NDI scores. Relative change was superior for NRS neck and arm pain scores and NDI, while absolute difference was superior for EQ-5D and EQ VAS scores. CONCLUSIONS Relative change and its corresponding MCIRC were found to be more appropriate as a surrogate of subjective satisfaction when studying the NRS and NDI scores, whereas absolute difference and MCID was more appropriate when addressing EQ-5D index and EQ VAS scores.

This study used semi-structured interviews with 11 key opinion leaders to explore why dermatologist involvement in innovation remains limited despite growing investment in the field. It found that barriers such as limited early exposure to industry, time constraints and goal misalignment hinder engagement, but also highlighted solutions like integrating industry exposure into training and fostering new funding models. These findings suggest actionable strategies to bridge gaps between clinicians and industry and promote dermatological innovation.

BACKGROUND: Whereas antiphospholipid syndrome (APS) is best known for increasing the risk of macrovascular thrombosis, APS vasculopathy is characterized by the abnormal proliferation of endothelial and smooth muscle cells, leading to occlusion of small blood vessels in the skin, kidneys, and heart, among other organs. The underlying mechanisms remain unclear, and targeted treatment options for patients with APS are lacking. METHODS: To identify and analyze APS microvascular endothelial cells (MVECs), skin biopsies of patients with APS complicated by livedo racemosa were characterized using single-cell RNA sequencing. CCN1 (cellular communication network factor 1) and CCN2 were identified in skin and kidney biopsies by immunofluorescence microscopy and in plasma by ELISA. Healthy dermal MVECs were cultured with APS patient–derived serum or immunoglobulin G (IgG), and relevant signaling pathways were characterized using quantitative PCR, immunoblotting, and immunofluorescence microscopy. The proliferation and migration of vascular smooth muscle cells were determined after exposure to conditioned medium from APS IgG–stimulated MVECs. A mouse model of APS IgG–accelerated neointima formation was developed. Anti-CCN2 monoclonal antibodies were tested in vascular smooth muscle cell functional assays and the mouse model. RESULTS: Increased endothelial cell expression of CCN1 and CCN2 was identified by single-cell RNA sequencing and further confirmed in APS skin by microscopy as well as in APS plasma by ELISA. Exposure of healthy MVECs to patient IgG triggered the upregulation of CCN1 and CCN2 via Toll-like receptor 4– and YAP1 (yes-associated protein 1)–mediated signaling. CCN2, originating from APS IgG–stimulated MVECs led to the proliferation and migration of vascular smooth muscle cells, phenotypes that were inhibited by an anti-CCN2 antibody or depletion of EGFR (epidermal growth factor receptor). We further observed increased expression of CCN2, along with evidence of YAP1 nuclear translocation, in kidney vessels of APS nephropathy biopsies. Finally, CCN2 inhibition with an anti-CCN2 monoclonal antibody significantly reduced neointima thickening and cell proliferation in a mouse model of APS IgG–accelerated neointima formation. CONCLUSIONS: This study revealed activation of YAP1-mediated signaling in APS dermal microvessels and demonstrated that the YAP1 target CCN2 plays a role in facilitating pro-proliferative communication between MVECs and vascular smooth muscle cells. These findings offer insights into the cellular and molecular mechanisms underlying APS vasculopathy, providing potential therapeutic targets for patients.

Abstract Despite significant therapeutic advances in multiple myeloma (MM), outcomes in patients with plasma cell leukemia (PCL) remain dismal. We conducted a multicenter retrospective analysis of patients with PCL who were treated with the B-cell maturation antigen–directed chimeric antigen receptor T-cell (CAR-T) products idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel). We identified 34 patients; 19 patients received ide-cel and 15 received cilta-cel. With a median follow-up of 11.9 months, the overall median progression-free survival (mPFS) was 9.0 months (95% confidence interval [CI], 4-15) and the median overall survival (mOS) was 13.0 months (95% CI, 8 to not estimable [NE]). The 1-year cumulative incidence of progression or death was 72%, and the 1-year cumulative incidence of death was 47%. Patients who received cilta-cel had a longer mPFS (19.0 months vs 6.0 months) and mOS (&gt;23 months [NE] vs 9.0 months) when compared with those treated with ide-cel. Similarly, the 1-year cumulative incidence of disease progression or death was 37.5% (95% CI, 17.4-68.5) with cilta-cel, whereas all patients treated with ide-cel progressed or died within 12 months of infusion. The rates of hematologic and nonhematologic toxicities were similar between patients treated with cilta-cel and those treated with ide-cel and were consistent with those reported in patients with MM. In this first multicenter study that evaluated patients with PCL who were treated with standard-of-care CAR-T products, we show that CAR-T is safe, feasible, and associated with improved outcomes when compared with historic standards.

Abstract Traumatic brain injury (TBI) can lead to chronic complications, including headache and facial hypersensitivity. Second-impact syndrome (SIS), occurring when a second TBI precedes recovery from an initial injury, often causes severe long-term symptoms. Neuroinflammation is implicated, but the comprehensive pathophysiology of SIS remains unclear. This study characterized neurological/behavioral outcomes, facial nociception, plasma inflammatory markers, and central nervous system (CNS) histopathology in rat models of SIS and single mild TBI. Female Wistar rats (n = 6/group) were assigned to naïve control, sham surgery, single impact (TBI), or double impact (SIS; intervals: 1h, 24h, 3d, 7d, 14d). Mild TBI was induced using a modified Marmarou weight-drop model. Assessments (facial mechanical sensitivity via von Frey, Neurological Severity Scale (NSS), Neurobehavioral Scale (NBS)) were performed pre-injury and on days 1,3,5,7 post-injury. Plasma IL-6 and TNF-α were measured by ELISA. Histopathology (H&E) assessed CNS inflammation. All impact groups developed transient facial mechanical allodynia and acute neurobehavioral deficits (impaired NSS/NBS at day 1). SIS groups, particularly with longer intervals (≥ 24h), exhibited more prolonged facial allodynia and significant neurological deficits compared to single TBI at specific timepoints. Plasma cytokines showed minimal changes. Histopathology revealed significantly elevated CNS inflammation in both TBI and SIS groups versus controls, with SIS groups (intervals 24h-14d) showing robust responses. Repeated TBI, especially with longer recovery intervals between injuries, results in more severe and prolonged facial allodynia, neurological deficits, and CNS neuroinflammation than a single mild TBI. These findings illuminate SIS pathophysiology and underscore the critical need for protection post-concussion.