Citations

Abstract Ovarian carcinosarcoma (OCS) is an aggressive and rare tumor type with limited treatment options. OCS is hypothesized to develop via the combination theory, with a single progenitor resulting in carcinomatous and sarcomatous components, or alternatively via the conversion theory, with the sarcomatous component developing from the carcinomatous component through epithelial-to-mesenchymal transition (EMT). In this study, we analyzed DNA variants from isolated carcinoma and sarcoma components to show that OCS from 18 women is monoclonal. RNA sequencing indicated that the carcinoma components were more mesenchymal when compared with pure epithelial ovarian carcinomas, supporting the conversion theory and suggesting that EMT is important in the formation of these tumors. Preclinical OCS models were used to test the efficacy of microtubule-targeting drugs, including eribulin, which has previously been shown to reverse EMT characteristics in breast cancers and induce differentiation in sarcomas. Vinorelbine and eribulin more effectively inhibited OCS growth than standard-of-care platinum-based chemotherapy, and treatment with eribulin reduced mesenchymal characteristics and N-MYC expression in OCS patient-derived xenografts. Eribulin treatment resulted in an accumulation of intracellular cholesterol in OCS cells, which triggered a downregulation of the mevalonate pathway and prevented further cholesterol biosynthesis. Finally, eribulin increased expression of genes related to immune activation and increased the intratumoral accumulation of CD8+ T cells, supporting exploration of immunotherapy combinations in the clinic. Together, these data indicate that EMT plays a key role in OCS tumorigenesis and support the conversion theory for OCS histogenesis. Targeting EMT using eribulin could help improve OCS patient outcomes. Significance: Genomic analyses and preclinical models of ovarian carcinosarcoma support the conversion theory for disease development and indicate that microtubule inhibitors could be used to suppress EMT and stimulate antitumor immunity.

Abstract Building medical microrobots from the body's own cells may circumvent the biocompatibility concern and hence presents more potential in clinical applications to improve the possibility of escaping from the host defense mechanism. More importantly, live cells can enable therapeutically relevant functions with significantly higher efficiency than synthetic systems. Here, live immune cell‐derived microrobots from macrophages, i.e., immunobots , which can be remotely steered with externally applied magnetic fields and directed toward anti‐tumorigenic (M1) phenotypes, are presented. Macrophages engulf the engineered magnetic decoy bacteria , composed of 0.5 µm diameter silica Janus particles with one side coated with anisotropic FePt magnetic nanofilm and the other side coated with bacterial lipopolysaccharide (LPS). This study demonstrates the torque‐based surface rolling locomotion of the immunobots along assigned trajectories inside blood plasma, over a layer of endothelial cells, and under physiologically relevant flow rates. The immunobots secrete signature M1 cytokines, IL‐12 p40, TNF‐α, and IL‐6, and M1 cell markers, CD80 and iNOS, via toll‐like receptor 4 (TLR4)‐mediated stimulation with bacterial LPS. The immunobots exhibit anticancer activity against urinary bladder cancer cells. This study further demonstrates such immunobots from freshly isolated primary bone marrow‐derived macrophages since patient‐derivable macrophages may have a strong clinical potential for future cell therapies in cancer.

Abstract Background The association of renin with adverse kidney outcomes is largely unknown, and renin measurement strategies vary. We aimed to measure the clinical correlates of different renin measurements and the association between renin and incident chronic kidney disease (CKD), end-stage kidney disease (ESKD), and mortality. Methods We performed a prospective cohort analysis of 9,420 participants in the Atherosclerosis Risk in Communities study followed from 1996 to 1998 through 2019. We estimated longitudinal associations of renin measured using SomaScan modified nucleotide aptamer assay with incident CKD, ESKD, and death using Cox proportional hazards models. Using samples from a subsequent study visit, we compared SomaScan renin with plasma renin activity (PRA) and renin level from Olink, and estimated associations with covariates using univariate and multivariable regression. Results Higher SomaScan renin levels were associated with a higher risk of incident CKD (hazard ratio per two-fold higher [HR], 1.14; 95% confidence interval [CI], 1.09 to 1.20), ESKD (HR, 1.20; 95% CI, 1.03 to 1.41), and mortality (HR, 1.08; 95% CI, 1.04 to 1.13) in analyses adjusted for demographic, clinical, and socioeconomic covariates. SomaScan renin was moderately correlated with PRA (r = 0.61) and highly correlated with Olink renin (r = 0.94). SomaScan renin and PRA had similar clinical correlates except for divergent associations with age and beta-blocker use, both of which correlated positively with SomaScan renin but negatively with PRA. Conclusions SomaScan aptamer-based renin level was associated with a higher risk of CKD, ESKD, and mortality. It was moderately correlated with PRA, sharing generally similar clinical covariate associations.

307 Background: In the US, more than 12,000 people die from ovarian cancer annually. Although new treatments have recently become available, ovarian cancer care delivery remains suboptimal. The Association of Community Cancer Centers (ACCC) developed a series of initiatives to improve the quality of care for patients with ovarian cancer. In Phase I, ACCC evaluated the needs of cancer programs, conducted 3 quality improvement (QI) workshops, and developed expert-driven Quality of Care recommendations to aid cancer programs in self-assessment and quality improvement. In Phase II, ACCC invited programs to self-assess their level of care using the Quality of Care recommendations. Methods: In 2022, ACCC surveyed 7 ovarian cancer programs across the US. Developed by a multidisciplinary expert steering committee, the 26-question survey assessed the patient populations served, services provided, diagnostic evaluations performed, access to molecular testing, and a self-assessment of quality care delivery and interest in conducting QI projects related to self-identified needs. The survey was administered in Qualtrics and summarized using descriptive statistics. Results: Surveys were completed by 1 community, 2 comprehensive community, 2 hospital-associated, 1 academic comprehensive, and 1 NCI-designated comprehensive cancer programs. The median annual ovarian cases was 40 [range: 2 to 68]. The 7 programs serve diverse racial/ethnic distribution of patients with ovarian cancer ranging from 55% Black to 60% Asian and 30% Pacific Islander. Five programs have a multidisciplinary team for ovarian cancer. All 5 multidisciplinary teams included gynecologic oncology and pathology; 3 teams also included medical oncology and or radiology colleague(s). Sites assessed their level of care for 7 domains of quality care from 1 (lowest) to 5 (highest). The average score was 4.0 for Care Coordination and Patient Education, Treatment Planning, and Disease Surveillance. Diagnosis and Initial Management scored on average 3.8, Equity in Care 3.25, Prevention and Screening 3.25, and Quality of Life 3.2. Sites ranked areas of interest for future QI projects (1 = area of most interest, 7 = area of least interest). The highest ranked domains were Care Coordination and Patient Education as well as Diagnosis and Initial management (average rankings 2.8). These were followed by Quality of Life (average 3.0), Prevention and Screening (Average 3.8), Treatment Planning (Average 4.4), Equity in Care (Average 5.0), and Disease Surveillance (Average 6.2). Conclusions: This assessment will be used to identify 4 additional sites for Phase II QI workshops. Findings from these projects will be combined, summarized, and disseminated to inform future education opportunities and QI initiatives. This initiative aims to help organize and standardize the care of patients with ovarian cancer and improve patient care coordination.

180 Background: Financial toxicity affects 20% of cancer survivors and is associated with decreased treatment adherence and poor clinical outcomes. No large-scale programs have been implemented to mitigate financial toxicity among patients undergoing cancer treatment. We evaluated the effect of monthly patient-reported financial toxicity screening as part of a larger digital monitoring intervention. Methods: PRO-TECT (AFT-39) is a cluster-randomized trial of patients undergoing systemic therapy for metastatic cancer. Practices were randomized 1:1 to digital symptom monitoring with patient-reported outcomes (“PRO practices”) or usual care (“control practices”). Digital monitoring consisted of between-visit online or automated telephone patient surveys containing symptom, functioning, and financial toxicity screening questions for up to one year, with automated alerts sent to practice nurses for concerning survey scores. Clinical team actions in response to alerts were not mandated. The primary outcome of this analysis was development or worsening of financial difficulties, assessed via the EORTC QLQ-C30 (“Has your physical condition or medical treatment caused you financial difficulties?”), at any time compared to baseline. A randomly selected subset of patients and nurses were interviewed about their experiences with the intervention. Results: 1,191 patients were enrolled (593 PRO; 598 control) at 52 US community oncology practices. Overall, 30.2% of patients treated at practices that received the intervention developed, or experienced worsening of, financial difficulties, compared to 39.0% of patients treated at control practices (p = 0.01). Patients and nurses interviewed stated that financial toxicity screening identified patients for financial counseling who otherwise would be reluctant to seek, or unaware of the availability of, assistance. Conclusions: Screening for financial toxicity as part of routine digital patient monitoring with PROs reduces the development, or worsening, of financial difficulties among patients undergoing systemic cancer therapy. Clinical trial information: NCT03249090.

Background: Surgical and nonoperative management of anterior cruciate ligament (ACL) injuries seek to mitigate the risk of knee instability and secondary meniscal injury. However, the associated risk and timing of secondary meniscal tears have not been completely elucidated. Purpose: To compare risk and timing of secondary meniscal injury between patients receiving nonoperative management, delayed ACL reconstruction (ACLR), and early ACLR using a machine learning survival analysis. Study Design: Cohort study; Level of evidence, 3. Methods: A geographic database was used to identify and review records of patients with a diagnosis of ACL rupture between 1990 and 2016 with minimum 2-year follow-up. Patients undergoing ACLR were matched 1:1 with nonoperatively treated controls. Rate and time to secondary meniscal tear were compared using random survival forest algorithms; independent models were developed and internally validated for predicting injury-free duration in both cohorts. Performance was measured using out-of-bag c-statistic, calibration, and Brier score. Model interpretability was enhanced using global variable importance and partial dependence curves. Results: The study included 1369 patients who underwent ACLR and 294 patients who had nonoperative treatment. After matching, no significant differences in rates of secondary meniscal tear were found ( P = .09); subgroup analysis revealed the shortest periods of meniscal survival in patients undergoing delayed ACLR. The random survival forest algorithm achieved excellent predictive performance for the ACLR cohort, with an out-of-bag c-statistic of 0.80 and a Brier score of 0.11. Significant variables for risk of meniscal tear for the ACLR cohort included time to return to sports or activity ≤350 days, time to surgery ≥50 days, age at injury ≤40 years, and high-impact or rotational landing sports, whereas those in the nonoperative cohort model included time to RTS ≤200 days, visual analog scale pain score >3 at consultation, hypermobility, and noncontact sports. Conclusion: Delayed ACLR demonstrated the greatest long-term risk of meniscal injury compared with nonoperative treatment or early ACLR. Risk factors for decreased meniscal survival after ACLR included increased time to surgery, shorter time to return to sports or activity, older age at injury, and involvement in high-impact or rotational landing sports. Pending careful external validation, these models may be deployed in the clinical space to provide real-time insights and enhance decision making.

Abstract Objectives To establish a framework by which experts define disease subsets in systemic sclerosis associated interstitial lung disease (SSc-ILD). Methods A conceptual framework for subclinical, clinical and progressive ILD was provided to 83 experts, asking them to use the framework and classify actual SSc-ILD patients. Each patient profile was designed to be classified by at least four experts in terms of severity and risk of progression at baseline; progression was based on 1-year follow-up data. A consensus was reached if ≥75% of experts agreed. Experts provided information on which items were important in determining classification. Results Forty-four experts (53%) completed the survey. Consensus was achieved on the dimensions of severity (75%, 60 of 80 profiles), risk of progression (71%, 57 of 80 profiles) and progressive ILD (60%, 24 of 40 profiles). For profiles achieving consensus, most were classified as clinical ILD (92%), low risk (54%) and stable (71%). Severity and disease progression overlapped in terms of framework items that were most influential in classifying patients (forced vital capacity, extent of lung involvement on high resolution chest CT [HRCT]); risk of progression was influenced primarily by disease duration. Conclusions Using our proposed conceptual framework, international experts were able to achieve a consensus on classifying SSc-ILD patients along the dimensions of disease severity, risk of progression and progression over time. Experts rely on similar items when classifying disease severity and progression: a combination of spirometry and gas exchange and quantitative HRCT.

Takotsubo cardiomyopathy or Takotsubo Syndrome (TTS) is a reversible left ventricular dysfunction syndrome that is increasingly being recognized. Recent advances in nuclear imaging have allowed us to study TTS in greater detail. We searched the PubMed and Medline databases and identified 53 publications with 221 patients reporting nuclear imaging findings in TTS. The age of the patients ranged from 17 to 87 years and were predominantly women (88.2%). The TTS variant was apical (typical) in 170 (76.9%), mid-ventricular in 23 (10.4%), and basal (reverse TTS) in 2 (0.9%). Cardiac perfusion was assessed using 99mTc sestamibi (MIBI) SPECT, 99mTc tetrofosmin SPECT, 201Tl SPECT, 82Rb PET, 201Tl SPECT, and 13N ammonia PET. Additional studies used were 123I MIBG SPECT, 123I BMIPP SPECT, 18F FDG PET, 67Ga citrate, and 11C hydroxy-ephedrine. A perfusion defect was seen in 69 (31.2%), and an inverse perfusion–metabolism mismatch (normal or near-normal perfusion with absent myocardial metabolic activity) was seen in 183 (82.8%) patients. Nuclear imaging has a significant role in evaluating, diagnosing, and prognosticating patients with TTS. As nuclear imaging technology evolves, we will surely gain more insights into this fascinating disorder.

Abstract Myeloid neoplasms and acute leukemias derive from the clonal expansion of hematopoietic cells driven by somatic gene mutations. Although assessment of morphology plays a crucial role in the diagnostic evaluation of patients with these malignancies, genomic characterization has become increasingly important for accurate diagnosis, risk assessment, and therapeutic decision making. Conventional cytogenetics, a comprehensive and unbiased method for assessing chromosomal abnormalities, has been the mainstay of genomic testing over the past several decades and remains relevant today. However, more recent advances in sequencing technology have increased our ability to detect somatic mutations through the use of targeted gene panels, whole-exome sequencing, whole-genome sequencing, and whole-transcriptome sequencing or RNA sequencing. In patients with myeloid neoplasms, whole-genome sequencing represents a potential replacement for both conventional cytogenetic and sequencing approaches, providing rapid and accurate comprehensive genomic profiling. DNA sequencing methods are used not only for detecting somatically acquired gene mutations but also for identifying germline gene mutations associated with inherited predisposition to hematologic neoplasms. The 2022 International Consensus Classification of myeloid neoplasms and acute leukemias makes extensive use of genomic data. The aim of this report is to help physicians and laboratorians implement genomic testing for diagnosis, risk stratification, and clinical decision making and illustrates the potential of genomic profiling for enabling personalized medicine in patients with hematologic neoplasms.

Abstract Cellular senescence is a state of permanent growth arrest that plays an important role in wound healing, tissue fibrosis, and tumor suppression. Despite senescent cells’ (SnC) pathological role and therapeutic interest, their phenotype in vivo remains poorly defined. Here, we developed an in vivoderived senescence signature using a foreign body response (FBR) fibrosis model in a SnC reporter mouse. We identified pericytes and “cartilage-like” fibroblasts as senescent and defined cell typespecific senescence associated secretory phenotypes (SASP). Transfer learning and senescence scoring identified these two SnC populations along with endothelial and epithelial SnCs in new and publicly available murine and human data single cell RNAseq (scRNAseq) datasets from diverse pathologies. Signaling analysis uncovered crosstalk between SnCs and myeloid cells via an IL34- CSF1R-TGFßR signaling axis, contributing to tissue balance of vascularization and matrix production. Overall, our study provides a senescence signature and a computational approach that may be broadly applied to identify transcriptional profiles and SASP factors produced by SnCs that regulate tissue structure and pathology.