Degenerative Mitral Regurgitation Outcomes in Asian Compared With European-American Institutions.

Background: Clinical outcome and interventional thresholds for degenerative mitral regurgitation (DMR) were developed in studies of patients at European and American institutions (EAIs), but little is known about patients at Asian institutions (AsIs). Objectives: This study sought to contrast DMR presentation/management/outcomes of AsI patients vs EAI patients. Methods: Patients with DMR due to flail leaflet from Hong Kong and Singapore (AsI cohort, n = 737) were compared with EAI patients (n = 682) enrolled in the MIDA (Mitral regurgitation International Database) registry with similar eligibility criteria. Results: AsI patients presented similar DMR lesion/consequences vs EAI patients, but they were younger, with fewer symptoms (74% vs 44% Class I), more sinus rhythm (83% vs 69%), and lower EuroSCORE II (European System for Cardiac Operative Risk Evaluation II) (0.9 ± 0.5 vs 1.4 ± 1.5; all P < 0.0001). Imaging showed smaller absolute left atrial/ventricular dimensions in AsI patients, belying cardiac dilatation with larger body surface area-indexed diameters (all P < 0.01). Surgical/interventional mitral repair was similarly predominant (90% vs 91%; P = 0.47), and early repair was similarly beneficial (for AsI patients, adjusted HR: 0.28; 95% CI: 0.16-0.49; for EAI patients, HR: 0.32; 95% CI: 0.20-0.49; both P < 0.0001). However, AsI patients underwent fewer interventions (55% ± 2% vs 77% ± 2% at 1 year; P < 0.0001) and incurred excess mortality (adjusted HR: 1.60 [95% CI: 1.13-2.27] vs EAI patients; P = 0.008) at long-term postdiagnosis. Propensity score matching (434 patient pairs), which balanced all clinical characteristics, confirmed that there was undertreatment and excess mortality in the long term in AsI patients with DMR (P < 0.0001). Conclusions: Imaging may underestimate volume overload in AsI patients due to smaller cardiac cavities related to smaller body size compared with EAI patients with similar mitral lesions and DMR severity. AsI patients enjoy similar mitral repair predominance and early intervention benefits but undergo fewer mitral interventions than EAI patients and incur subsequent excess mortality, suggesting the need to account for imaging and cultural specificity to improve DMR outcomes worldwide.

SARS-CoV-2-Triggered Hemophagocytic Lymphohistiocytosis with Complications of Posterior Reversible Encephalopathy Syndrome.

In this article, we describe a novel case of SARS-CoV-2-associated-hemophagocytic lymphohistiocytosis (HLH) complicated by posterior reversible encephalopathy syndrome (PRES). Initially diagnosed with multisystem inflammatory response in children (MIS-C), the patient received a large corticosteroid dose days before the onset of neurological symptoms. After developing PRES, the patient was treated with antihypertensives, antiepileptics, dexamethasone, and anakinra, leading to neurologic normalization. We propose that given the challenging diagnostic picture of PRES developing in patients with HLH or MIS-C, institutionalized standards for blood pressure management during corticosteroid induction may significantly improve outcomes in patients being treated for hyperinflammatory syndromes who develop neurological symptoms.

Survival loss linked to guideline-based indications for degenerative mitral regurgitation surgery.

AIMS: Operating on patients with severe degenerative mitral regurgitation (DMR) is based on ACC/AHA or ESC/EACTS-guidelines. Doubts persist on best surgical indications and their potential association with postoperative survival loss. We sought to investigate whether guideline-based indications lead to late postoperative survival loss in DMR-patients. METHODS AND RESULTS: : We analyzed outcome of 2833 patients from the MIDA-registry undergoing surgical correction of DMR. Patients were stratified by surgical indications: Class-I-trigger (symptoms, left ventricular end-systolic diameter≥40mm, or left ventricular ejection fraction<60%, n=1677), isolated-Class-IIa-trigger (atrial fibrillation [AF], pulmonary hypertension [PH], or left atrial diameter≥55mm, n=568), or no-trigger (n=588). Postoperative survival was compared after matching for clinical differences. Restricted-mean-survival time (RMST) was analyzed. During a median 8.5-year follow-up, 603 deaths occurred. Long-term postoperative survival was lower with Class-I-trigger than in Class-IIa-trigger and no-trigger (71.4±1.9%, 84.3±2.3%, 88.9±1.9% at 10 years, p<0.001). Having at least one Class-I-criterion led to excess mortality (p<0.001), while several Class-I-criteria conferred additional death-risk (HR:1.53, 95%CI:1.42-1.66). Isolated-Class-IIa-triggers conferred an excess mortality risk versus those without (HR:1.46, 95%CI:1.00-2.13, p=0.05). Among these patients, isolated-PH led to decreased postoperative-survival versus those without (83.7%±2.8% vs. 89.3%±1.6%, p=0.011), with the same pattern observed for AF (81.8%±5.0% vs. 88.3%±1.5%, p=0.023). According to RMST-analysis, compare to those operated on without triggers, operating on Class-I-trigger patients led to 9.4-month survival-loss (p<0.001) and operating on isolated-Class-IIa-trigger patients displayed 4.9-month survival loss (p=0.001) after 10-years. CONCLUSIONS: : Waiting for the onset of Class-I or isolated-Class-IIa-triggers before operating on DMR patients is associated with postoperative survival loss. These data encourage an early surgical-strategy.

Pharmacologic inhibition of eIF4A blocks NRF2 synthesis to prevent osteosarcoma metastasis.

PURPOSE: Effective therapies for metastatic osteosarcoma (OS) remain a critical unmet need. Targeting mRNA translation in metastatic OS offers a promising option, as selective translation drives synthesis of cytoprotective proteins under harsh microenvironmental conditions to facilitate metastatic competence. EXPERIMENTAL DESIGN: We assessed expression levels of eukaryotic translation factors in OS, revealing high expression of the eIF4A1 initiation factor. Using a panel of metastatic OS cell lines and PDX models, eIF4A1 inhibitors were evaluated for their ability to block proliferation and reduce survival under oxidative stress, mimicking harsh conditions of the lung microenvironment. Inhibitors were also evaluated for their anti-metastatic activity using the ex vivo pulmonary metastasis assay (PuMA) and in vivo metastasis models. Proteomics were performed to catalog which cytoprotective proteins or pathways were affected by eIF4A1 inhibition. RESULTS: CR-1-31B, a rocaglate-based eIF4A1 inhibitor, exhibited nanomolar cytotoxicity against all metastatic OS models tested. CR-1-31B exacerbated oxidative stress and apoptosis when OS cells were co-treated with a tert-butylhydroquinone (tBHQ), a chemical oxidative stress inducer. CR-1-31B potently inhibited OS growth in the PuMA model and in experimental and spontaneous models of OS lung metastasis. Proteomic analysis revealed that tBHQ-mediated upregulation of the NRF2 antioxidant factor was blocked by co-treatment with CR-1-31B. Genetic inactivation of NRF2 phenocopied the anti-metastatic activity of CR-1-31B. Finally, the clinical grade eIF4A1 phase 1-2 inhibitor, Zotatifin, similarly blocked NRF2 synthesis and the OS metastatic phenotype. CONCLUSIONS: Collectively, our data reveal that pharmacologic targeting of eIF4A1 is highly effective in blocking OS metastasis by blunting the NRF2 antioxidant response.

Changes in left ventricular-aortic angulation are associated with the development of obstruction in hypertrophic cardiomyopathy.

OBJECTIVE: To characterize changes in ventricular morphology in patients with hypertrophic cardiomyopathy who develop left ventricular (LV) outflow tract obstruction. METHODS: We reviewed patients with hypertrophic cardiomyopathy with LV outflow tract obstruction who underwent septal myectomy from May 2012 to June 2023. Among 68 patients initially without obstruction documented up to 7.6 years (interquartile range, 6.3-9.4 years) before the operation, a comparison was made with 78 patients with nonobstructive hypertrophic cardiomyopathy over a similar period. Patients who did not develop obstruction were matched with those who did on sex, age, and maximum septal wall thickness during the initial echocardiography, identifying 41 matched pairs. Echocardiographic data, including 5 measures of angulation, were compared between the groups. RESULTS: The median interval between echocardiographic assessments was 7.5 years (interquartile range, 6.3-8.1 years) among patients with obstruction versus 7.3 years (interquartile range, 6.2-9.0 years) in patients without nonobstruction. Patients with obstruction were more likely to have hypertension at both times. The maximum septal wall thickness increased within both groups (both P values < .001), but the magnitude of increase was not different between groups (P = .130). Patients with obstruction exhibited a greater increase in LV mass (P < .001) compared with patients without obstruction (P = .004). Aortic angulation significantly increased in 4 of the 5 measurements (all P values < .001) in patients with obstruction, whereas patients with no obstruction showed no change. Anterior and posterior mitral valve leaflet lengths and coaptation lengths remained similar in both groups over time. CONCLUSIONS: The development of LV outflow tract obstruction in patients with hypertrophic cardiomyopathy was associated with progressive LV outflow tract angulation and increased LV hypertrophy, as reflected by LV mass. Progression to obstruction was not related to changes in the mitral valve leaflet morphology.

The Asian Fabry Cardiomyopathy High-Risk Screening Study 2 (ASIAN-FAME-2): Prevalence of Fabry Disease in Patients with Left Ventricular Hypertrophy.

Background: Fabry disease (FD) is a rare X-linked lysosomal storage disorder that commonly manifests cardiovascular complications. We aimed to assess the prevalence of FD in a Chinese population with left ventricular hypertrophy (LVH) whilst implementing a gender-specific screening approach. Methods: Patients with LVH, defined as a maximum thickness of the left ventricular septal/posterior wall ≥ 13 mm, were considered eligible. All patients with hypertrophic cardiomyopathy (HCM) were excluded. Plasma α-galactosidase (α-GLA) enzyme activity was assessed using a dried blood spot test. Males with low enzyme activity underwent genetic testing to confirm a diagnosis of FD whereas females were screened for both α-GLA and globotriaosylsphingosine concentration and underwent genetic analysis of the GLA gene only if testing positive for ≥1 parameter. Results: 426 unrelated patients (age = 64.6 ± 13.0 years; female: male = 113:313) were evaluated. FD was diagnosed in 3 unrelated patients (age = 69.0 ± 3.5 years, female: male = 1:2) and 1 related female subject (age = 43 years). Genetic analyses confirmed the late-onset cardiac variant GLA c.640-801G>A (n = 3) and the missense variant c.869T>C associated with classic FD (n = 1). Cardiac complications were the only significant findings associated with the late-onset c.640-801G>A mutation, manifesting as mild or severe concentric LVH. In contrast, the classic c.869T>C mutation FD exhibited multisystemic manifestations in addition to severe concentric LVH. Conclusions: The prevalence of FD is lower in Chinese patients with LVH when HCM is excluded. The pathological variant c.640-801G>A remains the most common cause of late-onset FD, while the detection of FD in females can be improved by utilizing a gender-specific screening method.

A scoping review of unexpected weight loss and cancer: risk, guidelines, and recommendations for follow-up in primary care.

BACKGROUND: Cancer diagnoses often begin with consultations with general practitioners (GPs), but the nonspecific nature of symptoms can lead to delayed diagnosis. Unexpected weight loss (UWL) is a common nonspecific symptom linked to undiagnosed cancer, yet guidelines for its diagnostic assessment in general practice lack consistency. AIM: To synthesise evidence on the association between UWL and cancer diagnosis, and to review clinical guidelines and recommendations for assessing patients with UWL. DESIGN AND SETTINGS: Systematic search and analysis of studies conducted in primary care. METHOD: Four databases searched for peer-reviewed literature from 2012 to 2023. Two reviewers conducted all the steps. A narrative review was conducted detailing the evidence for UWL as a risk factor for undiagnosed cancer, existing clinical guidance, and recommended diagnostic approach. RESULTS: We included 25 studies involving 916,092 patients; 92% provided strong evidence of an association between UWL and undiagnosed cancer. The National Institute for Health Care and Excellence Cancer Guideline in the UK was frequently cited. General suggestions encompassed regular weight monitoring, family history, risk factor evaluation, additional signs and symptoms, and a comprehensive physical examination. Commonly recommended pathology tests included C-reactive protein, complete blood count, alkaline phosphatase, and thyroid-stimulating hormone. Immunochemical faecal occult blood test, abdominal ultrasound, and chest X-ray were also prevalent. One large cohort study provided age, sex, and differential diagnosis-specific recommendations. CONCLUSION: This evidence review informs recommendations for investigating patients with UWL and will contribute to a computer decision support tool implementation in primary care, enhancing UWL assessment and potentially facilitating earlier cancer diagnosis.

Frontotemporal lobar degeneration targets brain regions linked to expression of recently evolved genes.

In frontotemporal lobar degeneration (FTLD), pathological protein aggregation in specific brain regions is associated with declines in human-specialized social-emotional and language functions. In most patients, disease protein aggregates contain either TDP-43 (FTLD-TDP) or tau (FTLD-tau). Here, we explored whether FTLD-associated regional degeneration patterns relate to regional gene expression of human accelerated regions (HARs), conserved sequences that have undergone positive selection during recent human evolution. To this end, we used structural neuroimaging from patients with FTLD and human brain regional transcriptomic data from controls to identify genes expressed in FTLD-targeted brain regions. We then integrated primate comparative genomic data to test our hypothesis that FTLD targets brain regions linked to expression levels of recently evolved genes. In addition, we asked whether genes whose expression correlates with FTLD atrophy are enriched for genes that undergo cryptic splicing when TDP-43 function is impaired. We found that FTLD-TDP and FTLD-tau subtypes target brain regions with overlapping and distinct gene expression correlates, highlighting many genes linked to neuromodulatory functions. FTLD atrophy-correlated genes were strongly enriched for HARs. Atrophy-correlated genes in FTLD-TDP showed greater overlap with TDP-43 cryptic splicing genes and genes with more numerous TDP-43 binding sites compared with atrophy-correlated genes in FTLD-tau. Cryptic splicing genes were enriched for HAR genes, and vice versa, but this effect was due to the confounding influence of gene length. Analyses performed at the individual-patient level revealed that the expression of HAR genes and cryptically spliced genes within putative regions of disease onset differed across FTLD-TDP subtypes.

LncRNA MFRL regulates the phenotypic switch of vascular smooth muscle cells to attenuate arterial remodeling by encoding a novel micropeptide MFRLP.

BACKGROUND: Arterial remodeling is a common pathophysiological change in the pathogenesis of cardiovascular diseases in which the phenotypic switch of vascular smooth muscle cells (VSMC) plays an important role. Recently, an increasing number of long non-coding RNAs(lncRNAs) have been shown to encode micropeptides that play biological roles and have great clinical transformation potential. However, the role of micropeptides encoded by lncRNAs in arterial remodeling has not been well studied and requires further exploration. METHODS AND RESULTS: Through bioinformatic analysis and experimental verification, we found that a new lncRNA, the mitochondrial function-related lncRNA (MFRL), encodes a 64-amino acid micropeptide, MFRLP. MFRL and MFRLP play important roles in the phenotypic switch of VSMC. Further experiments showed that MFRLP interacts with mitochondrial cytochrome b to reduce accumulation of reactive oxygen species, suppress mitophagy and inhibit the VSMC switch from contractile to synthetic phenotype. CONCLUSIONS: LncRNA MFRL encodes the micropeptide MFRLP, which interacts with mitochondrial cytochrome b to inhibit the VSMC switch from contractile to synthetic phenotype and improve arterial remodeling.

Efficacy of the Allosteric MEK Inhibitor Trametinib in Relapsed and Refractory Juvenile Myelomonocytic Leukemia: a Report from the Children's Oncology Group.

Juvenile myelomonocytic leukemia (JMML) is a hematologic malignancy of young children caused by mutations that increase Ras signaling output. Hematopoietic stem cell transplantation (HSCT) is a potentially curative treatment, but patients with relapsed or refractory (advanced) disease have dismal outcomes. This phase II trial evaluated the safety and efficacy of trametinib, an oral MEK1/2 inhibitor, in patients with advanced JMML. Ten infants and children were enrolled, and the objective response rate was 50%. Four patients with refractory disease proceeded to HSCT after receiving trametinib. Three additional patients completed all 12 cycles permitted on study and continue to receive off-protocol trametinib without HSCT. The remaining three patients had progressive disease with two demonstrating molecular evolution by the end of cycle 2. Transcriptomic and proteomic analyses provided novel insights into the mechanisms of response and resistance to trametinib in JMML. ClinicalTrials.gov Identifier: NCT03190915. Significance: Trametinib was safe and effective in young children with relapsed or refractory JMML, a lethal disease with poor survival rates. Seven of 10 patients completed the maximum 12 cycles of therapy or used trametinib as a bridge to HSCT and are alive with a median follow-up of 24 months.

Radiofrequency ablation compared to surgery for thyroid nodules: A case for office based treatment.

Objective: We aim to evaluate the safety and effectiveness of radiofrequency ablation (RFA) for benign thyroid nodules by ENT surgeons and to compare it to conventional hemithyroidectomy in the public healthcare, operating theater contained setting. Methods: 50 patients who underwent a single session of RFA for symptomatic benign thyroid nodules in Prince of Wales Hospital and Tseung Kwan O Hospital in Hong Kong from 2020 to 2022 were evaluated. Objective outcomes including nodule volume, volume reduction rate (VRR) and complications were recorded. Subjective response in the form of a 0-10 point scale for patient symptoms including obstructive, cosmetic, pain and satisfaction scores were collected. Results: Significant reduction in mean VRR was found at 3, 6 and 12 months post treatment, accompanied by a significant reduction in the mean obstructive and cosmetic symptom scores. Comparing with conventional hemithyroidectomy, the RFA group had a significantly shorter mean procedure time and lower rate of complications. Estimated cost to patient for RFA was found to be less than half of that of hemithyroidectomy. Conclusion: RFA is a safe and effective treatment modality for benign thyroid nodules by ENT surgeons with advantages of being a scarless local anesthetic procedure with shorter procedure time, lower complication rate and lower cost to patient compared to hemithyroidectomy. In Hong Kong, where most of the population is treated in the public sector, there are limited resources, often with high caseload burden and long operation waiting times. Therefore, RFA is an office-based treatment that serves as a valuable alternative to hemithyroidectomy for benign nodules, especially in lower resource settings. Level of evidence: 3.

Restricted cusp motion in newly implanted tricuspid bioprostheses: Incidence, predictors, and impact on survival.

OBJECTIVE: To investigate the occurrence of restricted cusp motion (RCM) at the time of bioprosthetic tricuspid valve replacement (TVR) and analyze associated risk factors and outcomes. METHODS: This study involved adult patients who underwent TVR with a bioprosthesis at our institution between 2012 and 2022. Bioprosthetic cusp motion was analyzed de novo through a detailed review of intraoperative transesophageal echocardiograms (TEE). Two models of porcine valves were implanted: the Medtronic Hancock II bioprosthesis and the St Jude Medical Epic bioprosthesis. RESULTS: Among the 476 patients who met the inclusion criteria, RCM was identified on immediate post-bypass TEE in 150 (31.5%); there was complete immobility of the cusp in 63 patients (13.2%) and limited movement of a cusp in 87 patients (18.3%). In a multivariable logistic regression analysis, the Hancock II model (odds ratio [OR], 6.15; P < .001), a larger orifice area (per IQR increase: OR, 1.58; P = .017), a smaller body surface area (per IQR increase: OR, .68; P = .040), and a lower ejection fraction (per IQR increase: OR, .60; P = .033) were independently associated with having RCM. Cox regression adjusting for 15 covariates revealed that RCM at the time of TVR was independently associated with an increased risk of mortality (hazard ratio, 1.35; P = .049). CONCLUSIONS: This study revealed a high incidence of RCM in bioprosthetic valves in the tricuspid position detected shortly postimplantation, which was associated with increased late mortality. To reduce the probability of RCM, it is important to select the appropriate prosthesis model and size, particularly in small patients.

Metabolic Reprogramming of Tumor-Associated Macrophages Using Glutamine Antagonist JHU083 Drives Tumor Immunity in Myeloid-Rich Prostate and Bladder Cancers.

Glutamine metabolism in tumor microenvironments critically regulates antitumor immunity. Using the glutamine-antagonist prodrug JHU083, we report potent tumor growth inhibition in urologic tumors by JHU083-reprogrammed tumor-associated macrophages (TAMs) and tumor-infiltrating monocytes. We show JHU083-mediated glutamine antagonism in tumor microenvironments induced by TNF, proinflammatory, and mTORC1 signaling in intratumoral TAM clusters. JHU083-reprogrammed TAMs also exhibited increased tumor cell phagocytosis and diminished proangiogenic capacities. In vivo inhibition of TAM glutamine consumption resulted in increased glycolysis, a broken tricarboxylic acid (TCA) cycle, and purine metabolism disruption. Although the antitumor effect of glutamine antagonism on tumor-infiltrating T cells was moderate, JHU083 promoted a stem cell-like phenotype in CD8+ T cells and decreased the abundance of regulatory T cells. Finally, JHU083 caused a global shutdown in glutamine-utilizing metabolic pathways in tumor cells, leading to reduced HIF-1α, c-MYC phosphorylation, and induction of tumor cell apoptosis, all key antitumor features. Altogether, our findings demonstrate that targeting glutamine with JHU083 led to suppressed tumor growth as well as reprogramming of immunosuppressive TAMs within prostate and bladder tumors that promoted antitumor immune responses. JHU083 can offer an effective therapeutic benefit for tumor types that are enriched in immunosuppressive TAMs.

Data-driven fine-grained region discovery in the mouse brain with transformers.

Technologies such as spatial transcriptomics offer unique opportunities to define the spatial organization of the mouse brain. We developed an unsupervised training scheme and novel transformer-based deep learning architecture to detect spatial domains across the whole mouse brain using spatial transcriptomics data. Our model learns local representations of molecular and cellular statistical patterns which can be clustered to identify spatial domains within the brain from coarse to fine-grained. Discovered domains are spatially regular, even with several hundreds of spatial clusters. They are also consistent with existing anatomical ontologies such as the Allen Mouse Brain Common Coordinate Framework version 3 (CCFv3) and can be visually interpreted at the cell type or transcript level. We demonstrate our method can be used to identify previously uncatalogued subregions, such as in the midbrain, where we uncover gradients of inhibitory neuron complexity and abundance. Notably, these subregions cannot be discovered using other methods. We apply our method to a separate multi-animal whole-brain spatial transcriptomic dataset and show that our method can also robustly integrate spatial domains across animals.

Baseline characteristics of patients with heart failure with mildly reduced or preserved ejection fraction: The FINEARTS-HF trial.

AIMS: To describe the baseline characteristics of participants in the FINEARTS-HF trial, contextualized with prior trials including patients with heart failure (HF) with mildly reduced and preserved ejection fraction (HFmrEF/HFpEF). The FINEARTS-HF trial is comparing the effects of the non-steroidal mineralocorticoid receptor antagonist finerenone with placebo in reducing cardiovascular death and total worsening HF events in patients with HFmrEF/HFpEF. METHODS AND RESULTS: Patients with symptomatic HF, left ventricular ejection fraction (LVEF) ≥40%, estimated glomerular filtration rate ≥ 25 ml/min/1.73 m2, elevated natriuretic peptide levels and evidence of structural heart disease were enrolled and randomized to finerenone titrated to a maximum of 40 mg once daily or matching placebo. We validly randomized 6001 patients to finerenone or placebo (mean age 72 ± 10 years, 46% women). The majority were New York Heart Association functional class II (69%). The baseline mean LVEF was 53 ± 8% (range 34-84%); 36% of participants had a LVEF <50% and 64% had a LVEF ≥50%. The median N-terminal pro-B-type natriuretic peptide (NT-proBNP) was 1041 (interquartile range 449-1946) pg/ml. A total of 1219 (20%) patients were enrolled during or within 7 days of a worsening HF event, and 3247 (54%) patients were enrolled within 3 months of a worsening HF event. Compared with prior large-scale HFmrEF/HFpEF trials, FINEARTS-HF participants were more likely to have recent (within 6 months) HF hospitalization and greater symptoms and functional limitations. Further, concomitant medications included a larger percentage of sodium-glucose cotransporter 2 inhibitors and angiotensin receptor-neprilysin inhibitors than previous trials. CONCLUSIONS: FINEARTS-HF has enrolled a broad range of high-risk patients with HFmrEF and HFpEF. The trial will determine the safety and efficacy of finerenone in this population.

Early LAAO device migration after combined atrial fibrillation ablation and left atrial appendage occlusion.

The combined procedure of catheter ablation and percutaneous left atrial appendage occlusion for patients with atrial fibrillation has been shown to be safe and feasible using radiofrequency energy or cryoballoon.

The CLCF1-CNTFR axis drives an immunosuppressive tumor microenvironment and blockade enhances the effects of established cancer therapies.

Tumors comprise a complex ecosystem consisting of many cell types that communicate through secreted factors. Targeting these intercellular signaling networks remains an important challenge in cancer research. Cardiotrophin-like cytokine factor 1 (CLCF1) is an interleukin-6 (IL-6) family member secreted by cancer-associated fibroblasts (CAFs) that binds to ciliary neurotrophic factor receptor (CNTFR), promoting tumor growth in lung and liver cancer1,2. A high-affinity soluble receptor (eCNTFR-Fc) that sequesters CLCF1 has anti-oncogenic effects3. However, the role of CLCF1 in mediating cell-cell interactions in cancer has remained unclear. We demonstrate that eCNTFR-Fc has widespread effects on both tumor cells and the tumor microenvironment and can sensitize cancer cells to KRAS inhibitors or immune checkpoint blockade. After three weeks of treatment with eCNTFR-Fc, there is a shift from an immunosuppressive to an immunostimulatory macrophage phenotype as well as an increase in activated T, NKT, and NK cells. Combination of eCNTFR-Fc and αPD1 was significantly more effective than single-agent therapy in a syngeneic allograft model, and eCNTFR-Fc sensitizes tumor cells to αPD1 in a non-responsive GEM model of lung adenocarcinoma. These data suggest that combining eCNTFR-Fc with KRAS inhibition or with αPD1 is a novel therapeutic strategy for lung cancer and potentially other cancers in which these therapies have been used but to date with only modest effect. Overall, we demonstrate the potential of cancer therapies that target cytokines to alter the immune microenvironment.

Risk-based lung cancer screening performance in a universal healthcare setting.

Globally, lung cancer is the leading cause of cancer death. Previous trials demonstrated that low-dose computed tomography lung cancer screening of high-risk individuals can reduce lung cancer mortality by 20% or more. Lung cancer screening has been approved by major guidelines in the United States, and over 4,000 sites offer screening. Adoption of lung screening outside the United States has, until recently, been slow. Between June 2017 and May 2019, the Ontario Lung Cancer Screening Pilot successfully recruited 7,768 individuals at high risk identified by using the PLCOm2012noRace lung cancer risk prediction model. In total, 4,451 participants were successfully screened, retained and provided with high-quality follow-up, including appropriate treatment. In the Ontario Lung Cancer Screening Pilot, the lung cancer detection rate and the proportion of early-stage cancers were 2.4% and 79.2%, respectively; serious harms were infrequent; and sensitivity to detect lung cancers was 95.3% or more. With abnormal scans defined as ones leading to diagnostic investigation, specificity was 95.5% (positive predictive value, 35.1%), and adherence to annual recall and early surveillance scans and clinical investigations were high (>85%). The Ontario Lung Cancer Screening Pilot provides insights into how a risk-based organized lung screening program can be implemented in a large, diverse, populous geographic area within a universal healthcare system.

Hemodynamic Comparison of the On-X and Top Hat Mechanical Aortic Valve Prostheses.

BACKGROUND: There are limited data comparing hemodynamic valve function in mechanical aortic valve prostheses. This study compared the hemodynamic function of 2 commonly used mechanical aortic valve (AV) prostheses, the On-X (Artivion) and Top Hat (CarboMedics Inc) valves. METHODS: This study was a retrospective analysis of 512 patients who underwent AV replacement with the On-X (n = 252; 49%) or Top Hat (n = 260; 51%) mechanical valves between 2011 and 2019. Patients were matched on the basis of selected variables. Echocardiographic data were collected preoperatively and postoperatively over a median follow-up of 1.39 years. RESULTS: A total of 320 patients were matched, 160 patients in each group. Despite being matched for left ventricular outflow tract diameter, patients in the Top Hat group received a greater prevalence of smaller tissue annulus diameter valves (≤21 mm) (83% vs 38%; P < .001). Patients in the On-X group had longer aortic cross-clamp times (78 minutes vs 64 minutes; P < .001) during isolated aortic valve replacement. Discharge echocardiography showed no difference in the AV area index between both groups (1.00 cm2/m2 vs 1.02 cm2/m2; P = .377). During longer-term echocardiographic follow-up, the AV area index remained stable for both valves within their respective tissue annulus diameter groups (P = .060). CONCLUSIONS: There was no difference between the 2 valves with respect to the AV area index at discharge, and hemodynamic function was stable during longer-term follow-up. The longer aortic cross-clamp time observed in the On-X group may indicate increased complexity of implantation compared with the Top Hat group.

Calf rEF: Impact of Calf Muscle Pump Dysfunction With Reduced Ejection Fraction on All-Cause Mortality.

OBJECTIVE: To evaluate mortality outcomes by varying degrees of reduced calf muscle pump (CMP) ejection fraction (EF). PATIENTS AND METHODS: Consecutive adult patients who underwent venous air plethysmography testing at the Mayo Clinic Gonda Vascular Laboratory (January 1, 2012, through December 31, 2022) were divided into groups based on CMP EF for the assessment of all-cause mortality. Other venous physiology included measures of valvular incompetence and clinical venous disease (CEAP [clinical presentation, etiology, anatomy, and pathophysiology] score). Mortality rates were calculated using the Kaplan-Meier method. RESULTS: During the study, 5913 patients met the inclusion criteria. During 2.84-year median follow-up, there were 431 deaths. Mortality rates increased with decreasing CMP EF. Compared with EF of 50% or higher, the hazard ratios (95% CIs) for mortality were as follows: EF of 40% to 49%, 1.4 (1.0 to 2.0); EF of 30% to 39%, 1.6 (1.2 to 2.4); EF of 20% to 29%, 1.7 (1.2 to 2.4); EF of 10% to 19%, 2.4 (1.7 to 3.3) (log-rank P≤.001). Although measures of venous valvular incompetence did not independently predict outcomes, venous disease severity assessed by CEAP score was predictive. After adjusting for several clinical covariates, both CMP EF and clinical venous disease severity assessed by CEAP score remained independent predictors of mortality. CONCLUSION: Mortality rates are higher in patients with reduced CMP EF and seem to increase with each 10% decrement in CMP EF. The mortality mechanism does not seem to be impacted by venous valvular incompetence and may represent variables intrinsic to muscular physiology.