Citations

Background: The breathing cycle consists of abdominal breathing (AB), for which the diaphragm is responsible, and thoracic breathing (TB), generated by the intercostal muscles. Contraction of the two portions of the diaphragm accounts for 80% percent of inspiration. While bilateral diaphragmatic paralysis causes severe shortness of breath, hemidiaphragm paralysis (HDP) gives fewer symptoms at rest, making it difficult to recognize and diagnose. Because this condition is rare, little is known regarding its consequences on breathing efficiency. Hypothesis: Based on previous studies, we hypothesized that body positions substantially affect the efficiency of breathing in a patient with unilateral hemidiaphragm paralysis and the corresponding physiological parameters. Aims: To measure and compare the amplitudes of abdominal and chest movements in different body positions in an individual with HDP and measure parameters indicating breathing efficiency. Patient and Methods: The patient had HDP due to iatrogenic phrenic nerve injury. Changes in the circumference of the abdomen and chest were measured during inhalation and exhalation with respiratory plethysmography belts (placed on standardized reproducible positions on the chest and abdomen) in different body positions: sitting (SI), standing (ST), lying (SU) and prone (PR). Breathing frequency was calculated, and blood oxygen saturation (SpO2) was measured with a pulse oximeter. Results: The percentage (%) contributions of abdominal breathing were SI: 16.0; ST: 50.3; SU: −53.5; PR: 1.1. A negative sign shows paradoxical breathing. Blood oxygen saturation (SpO2) in the four positions was SI: 93%; ST: 93%; SU: 82%; and PR: 82%, whereas the respiratory rate (1/min) was SI:19.4; ST: 15.0; SU: 37.5; PR: 35.9. Conclusions: Body position markedly influences the relative contributions of abdominal and thoracic breathing and overall respiratory efficiency in patients with hemidiaphragm paralysis; abdominal breathing in the supine and prone positions is greatly reduced leading to decreased blood oxygen saturation, a compensatory increase in respiratory rate, and severe dyspnea even at rest.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Non-Small Cell Lung Cancer (NSCLC) provide recommendations for the treatment of patients with NSCLC, including diagnosis, primary disease management, surveillance, and subsequent treatment. The panel has updated the list of recommended targeted therapies based on recent FDA approvals and clinical data. This selection from the NCCN Guidelines for NSCLC focuses on treatment recommendations for advanced or metastatic NSCLC with actionable biomarkers.

ABSTRACT Sodium glucose co‐transporter 2 inhibitors (SGLT2i) and glucagon‐like peptide‐1 receptor agonists (GLP‐1 RAs) are nephroprotective and their use is recommended for adults with chronic kidney disease (CKD). The role of SGLT2i and GLP‐1 RAs in patients with acute kidney injury (AKI) is unknown. This systematic review aimed to estimate the effect of SGLT2i or GLP‐1 RAs on clinical outcomes in AKI. We systematically searched Embase, MEDLINE, Scopus, Web of Science Core Collection, and clinical trials registries for observational studies and clinical trials from database inception to July 3, 2025. Included studies evaluated adults (≥ 18 years) with AKI during a hospitalization and compared patients subsequently exposed to either SGLT2i or GLP‐1 RAs to a non‐exposed control group. Random effects meta‐analyses were performed. Six studies related to SGLT2i (five observational, one randomized trial) and one related to GLP‐1 RAs (one observational) met eligibility criteria ( N = 432,048 patients). SGLT2i/GLP‐1 RA exposure was associated with lower odds of major adverse kidney events (MAKE) (OR 0.63, 95% CI 0.46–0.86) and all‐cause mortality [odds ratio (OR) 0.36, 95% confidence interval (CI) 0.21–0.62] compared to controls. The odds for kidney replacement therapy were lower with SGLT2i therapy in the three studies where it was evaluated (OR 0.61, 95% CI 0.40–0.93). Sensitivity analyses restricted to SGLT2i data were consistent with the overall findings [MAKE OR 0.63 (95% CI 0.42–0.95); Mortality OR 0.34 (95% CI 0.18, 0.65)]. Exposure to SGLT2i or GLP‐1 RAs after AKI, examined primarily in observational studies, was associated with improved clinical outcomes. These findings are promising and warrant evaluation in randomized clinical trials.

Abstract The INFORM trial (NCT01670500) was a randomized, two-arm Phase II neoadjuvant study comparing the efficacy of a platinum-based regimen (cisplatin) versus an anthracycline (AC)-based regimen in participants with germline BRCA1/2 mutations and early-stage, HER2-negative breast cancer. MicroRNAs (miRNAs) are emerging as promising non-invasive biomarkers for disease detection and treatment monitoring. The initial aim of this study was to evaluate whether pretreatment plasma miRNA profiles were associated with treatment outcomes in the INFORM trial cohort. Pretreatment plasma samples from 97 INFORM participants (n=53 cisplatin and n=44 AC) were screened for 352 miRNAs commonly implicated in cancer using the qPCR-based ID3EALTM Cancer Panel. Twenty out of 53 participants achieved residual cancer burden (RCB) score of 0 or 1 with cisplatin and 20/44 with AC. Higher plasma miR-362-3p expression was associated with a favorable response to cisplatin (1.7-fold; p<0.01), but not to AC. MiR-362-3p expression in paired pretreatment tumor biopsies (n=79) did not significantly correlate with plasma expression and was not associated with RCB 0/1 (p>0.05). In TCGA, miR-362-3p expression was higher in breast tumors than in adjacent normal tissue, and higher in triple negative breast cancers (TNBCs) compared with hormone receptor-positive tumors (both FDR<0.001), independent of BRCA mutation or Single Base Substitution Signature 3 (SBS3) status. The miR-362-3p findings in INFORM did not replicate in a sister trial, TBCRC 030 (NCT01982448; 11 out of 46 cisplatin-treated patients achieved RCB 0/1, p=0.46). These results suggest that while miR-362-3p is unsuitable as a circulating biomarker for cisplatin response, it may play an important biological role in mediating cisplatin sensitivity in TNBCs, independent of BRCA1/2 mutations. Functional studies demonstrated that miR-362-3p is expressed and secreted by TNBC cell lines, operates as a tumor suppressor, and generally correlates with cisplatin sensitivity. Overexpression of miR-362-3p rendered MDA-MB-231 and CAL-51 cells cisplatin sensitive, while knockdown induced resistance in MDA-MB-436 cells. Ongoing studies are testing whether these effects translate in xenograft models. In silico and functional assays identified BCLAF1, a DNA damage response (DDR) regulator, as a direct target of miR-362-3p. Overexpression of miR-362-3p suppresses BCLAF1 mRNA and protein levels. Our findings demonstrate that miR-362-3p enhances cisplatin responsiveness by targeting BCLAF1. A miR-362-3p-based therapeutic may be useful as a co-agent to enhance tumor responses to platinum-based chemotherapy. Citation Format: Zhaoji Liu, Shizhong Ke, Xiaohui Li, Catherine Wu, Madison M. Uyemura, Brian R. Sardella, Erica S. Massicott, Lin Wang, Emily K. Aronson, Dimitra Karagkouni, Nikolas Kalavros, Ioannis S. Vlachos, Felipe Batalini, Cristina S. Bogsan, Jit Kong Cheong, Lihan Zhou, He Cheng, Phillip Munson, Erica L. Mayer, Judy E. Garber, Stuart J. Schnitt, Nadine M. Tung, Andrea L. Kasinski, Frank J. Slack, Gerburg M. Wulf, Yujing J. Heng. MiR-362-3p enhances platinum response in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7903.

Abstract Introduction Revascularization to prevent limb loss is not feasible or represents a very high risk in a significant proportion of patients with chronic limb-threatening ischaemia (CLTI). No standard definition currently exists to define this population of patients. The aim of this study was to develop a consensus-based, multidomain definition to improve clinical assessment and reporting of studies in people with ‘no option’ (NO) or ‘poor option’ (PO) CLTI. Methods A modified Delphi process was conducted with 164 specialists from 30 countries. Two iterative survey rounds were used to reach consensus, defined as ≥70% agreement with a score of ≥7 on a nine-point scale. Results Some 164 international vascular specialists participated in the study, averaging 19 years of experience. A multidomain framework including arterial disease anatomy, biology, risk, function, and context (ABRFC) achieved 83% consensus. A ‘desert foot’ was defined as the absence of distal arterial revascularization targets on advanced non-invasive imaging, invasive digital subtraction angiography, and at least one failed endovascular revascularization attempt (81.6% agreement). Inadequate autogenous bypass conduit was defined as the lack of usable autologous vein across all four limbs (85% agreement). Patients were classified as NO for revascularization if they present with ‘desert foot’, prohibitive medical risk, a non-functional limb, or in those patients who refused arterial revascularization. PO revascularization patients combined factors such as severe infection, lack of autologous vein, or treatment non-compliance (72.1% agreement). Conclusion This consensus study established a structured, expert-validated definition of no option or poor option for revascularisation of patients with CLTI. The multidomain ABRFC framework provides a foundation for standardized clinical assessment, trial design, and future guideline development.

Abstract Introduction: Detectable circulating tumor DNA (ctDNA) is associated with inferior outcomes in Ewing sarcoma (ES); however, ctDNA clears in nearly all patients within 2 of the 6 chemotherapy cycles before radiotherapy (RT) or surgery. Given a 3-year EFS of 37% on AEWS 1221 (metastatic) and 5-year EFS of 78% on AEWS 1031 (localized), current ctDNA testing fails to predict most relapses. Extracellular vesicles (EVs) are microscopic particles studied as a biomarker in multiple cancer types. We hope to improve the sensitivity of ctDNA in ES and provide the first application of EVs in ES. Methods: cfDNA was isolated from 1mL plasma, quantified by Qubit, and sequenced as NEBNext Enzymatic Methyl-seq v2 libraries. We performed a systematic unsupervised clustering analysis of 27 ES plasma cfDNA profiles using 4 differentially methylated regions (DMR) subsets (63 strong DMRs, top 30, top 15, and 10 promoter-proximal loci), 3 clustering algorithms (k-means, Ward hierarchical, PAM), and k=2-5 clusters, testing associations with tumor burden and progression. EV analysis involved antibody detection against ES surface markers, including LINGO1, ENPP1, CDH11, and CD99. Concentrations of EVs were determined by standardized and calibrated high-resolution flow cytometry then analyzed with custom-built software to automatically determine and apply gates. Samples were de-identified, randomly coded, and run in triplicates. The senior research technologist responsible for EV analysis was blinded to patient information and clinical data. Results: EV analysis included 36 pre-RT samples from 16 metastatic and 20 localized ES patients from a prospectively maintained biobank, with 27 pre-RT samples in the cfDNA analysis and 19 healthy donor (HD) samples. 35 of 36 patients had chemotherapy before sample collection. cfDNA concentrations were markedly elevated in ES patients compared with HD (24.4 vs 4.6 ng/mL, p<0.0001), and 74% of ES samples exceeded the HD 95th-percentile detectability threshold (7.0 ng/mL). Across clustering configurations, ES cfDNA profiles consistently exhibited reproducible methylation substructure. One configuration (PAM clustering, k = 5, 63 strong DMRs) showed a modest but permutation-supported association with primary tumor size (nominal p ≈ 0.04; empirical p ≈ 0.03-0.04). ES samples had increased EV concentration compared to HD (p<0.001), with AUC 0.988 for distinguishing between ES and HD ENPP1 (p<0.0001). The highest ENPP1 EV values were in patients with large primary tumors (>8 cm vs. ≤ 8cm) and metastatic disease (p=0.066). Conclusions: cfDNA- and EV-based liquid biopsy provide encouraging signals for high ES detectability pre-RT. We also show the first study of EVs as a novel biomarker in ES, which may provide complementary information to ctDNA. Multimodal liquid biopsy in ES may identify candidate patients for systemic or local therapy escalation and facilitate personalized care. Citation Format: Roman O. Kowalchuk, Lilli J. Greiner, Yohan Kim, Rubia Noori, Jeffrey Szymanski, William S. Harmsen, Pradeep S. Chauhan, Adam C. Amundson, Andrea M. McMahon, Peter J. Schoettler, Wendy A. Allen-Rhoades, Stephanie F. Polites, Peter S. Rose, Kelly M. Bailey, Linda M. McAllister-Lucas, Anita Mahajan, Fabrice Lucien-Matteoni, Nadia N. Laack, Aadel A. Chaudhuri. Multimodal liquid biopsy of Ewing sarcoma reveals high sensitivity prior to radiotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1149.

Abstract Professional identity is defined as the attitudes, behaviors, values, and experiences by which individuals define themselves in a professional role and is influenced by socialization during training and in the workplace. As professional identity develops and is integrated with one's personal identities, it allows an individual to think, act, and feel like a member of their chosen profession and to develop a sense of meaning, confidence, and satisfaction in their work. Conflicts may arise due to perceived differences between one's professional identity and the collective identity of the profession, resulting in stress, burnout, and attrition, all of which can negatively impact patient care and the collective identity of the genetic counseling profession. Using Social Identity Theory (SIT) as a theoretical framework to develop the semi‐structured interview protocol, recorded interviews were conducted with 50 genetic counselors who were purposefully sampled to ensure diversity of personal demographics (gender, race/ethnicity, sexual orientation, disability, and caregiver status), as well as years, settings, and roles in genetic counseling practice. Transcripts were coded and subjected to codebook thematic analysis using NVivo. Genetic counselors described their professional identity in terms of who they are (characteristics and attributes), what they do (actions and skills), and what they have (training and knowledge). The majority of participants had a multidimensional perspective of what it means to be a genetic counselor, noting the transferability of their skills to a broad set of roles and settings, which supported their sense of professional identity, particularly for those who were no longer seeing patients. Yet many expressed tension with the collective identity of the profession. Expanded opportunities for genetic counselors to work in new settings and roles require review and revision of key professional documents to ensure they are reflective of the collective identity of the genetic counseling profession.

Abstract Context Crinecerfont, a first-in-class corticotropin-releasing factor type 1 receptor antagonist, is FDA-approved as an adjunct to the physiologic glucocorticoid (GC) required to treat the underlying adrenal insufficiency in patients (≥4 years old) with classic congenital adrenal hyperplasia (CAH). By reducing elevated adrenocorticotropic hormone, crinecerfont controls excess adrenal androgens, thereby enabling lower GC doses. However, there are no published recommendations for how to reduce supraphysiologic GC doses after initiating crinecerfont. This manuscript aims to provide a framework developed by experienced endocrinologists for reducing supraphysiologic GC doses in patients taking crinecerfont. Evidence Acquisition An experienced panel of 11 endocrinologists discussed strategies and considerations when reducing GC doses and developed an algorithm to guide GC dose reductions after introducing crinecerfont in adults with CAH. Evidence Synthesis Approaches to GC reduction should be individualized based on the patient's therapeutic goals, cortisol needs, lifestyle preferences, and the clinician's experience to set appropriate targets for clinical parameters, androgens, and GC dose regimen. In general, GC doses should be reduced gradually to minimize the risks of developing symptoms of GC withdrawal or adrenal insufficiency. GC doses should be adjusted to the lowest level needed to maintain androgens at goal, without reducing below what is needed for cortisol replacement. Practical considerations during GC dose reduction include switching from longer- to shorter-acting GCs (eg, from dexamethasone to hydrocortisone), optimizing dose distribution to mimic normal circadian cortisol exposure, and consolidating or eliminating doses to improve adherence. Conclusion This framework for reducing supraphysiologic GC doses in adult patients taking crinecerfont may become increasingly relevant as treatment of CAH shifts toward physiologic GC replacement with adjunctive control of adrenal androgens.