Citations

Background: Aortic regurgitation (AR) is a prevalent valve disease with a long latent period to symptoms. Recent data has suggested the role of novel markers of myocardial overload in assessing onset of decompensation. Method: We sought to evaluate the role of unsupervised cluster analyses in identifying different clinical clusters, including clinical status, and a large number of echocardiographic variables including left ventricular (LV) volumes, and their association with mortality. Patients with ≥moderate-severe chronic AR identified using echocardiography at Mayo Clinic, Rochester were retrospectively analyzed. Primary outcome was all-cause mortality censored at aortic valve surgery/last follow-up. Uniform Manifold Approximation and Projection (UMAP) with K -means algorithm was used to cluster patients using clinical and, echocardiographic variables at the time of presentation. Missing data were imputed with the Multiple Imputation by Chained Equations (MICE) method. A supervised approach trained on the training set was used to find cluster membership in a hold-out validation set. Log-rank tests were used to assess differences in mortality rates between the clusters, both in the training and validation sets. Results: Three distinct clusters were identified among 1100 patients (log-rank P for survival <0.001). Cluster 1 (n=337), which included younger males with severe AR but fewer symptoms, showed the best survival, 75.6% (69.5, 82.3). Cluster 2 (n=235), older and more females with elevated filling pressures, showed intermediate survival of 64.2 % (56.8, 72.5). Cluster 3 (n=253), characterized by severe symptomatic AR, demonstrated the lowest survival of 45.3 % (34.4, 59.8) at 5 years. Similar clusters were formed in the internal validation cohort. Conclusion: Distinct clusters with variable echocardiographic features and mortality differences exist within patients with chronic ≥moderate-severe AR. Recognizing these clusters can refine individual risk stratification and clinical decision-making after verification in future prospective studies.

Background: Optimum timing of surgery for severe primary mitral regurgitation (MR) particularly in the absence of significant symptoms or echo evidence of LV impairment remains unclear. Other modalities of assessment include cardiopulmonary exercise testing (CPET) and novel echo measurements, such as LV global longitudinal strain (LVGLS). We sought to evaluate whether pre-op CPET or LVGLS are associated with survival after surgery. Methods: We identified consecutive patients who had surgery for severe primary MR between 2007 and 2017 and had pre-op CPET. Clinical and mortality data were collected from chart review and our institutional database. LVGLS was retrospectively collected by a single person blinded to patient outcomes. Primary outcome was post surgery all cause death, and we used univariable analysis to identify variables associated with all cause death. Results: We included 176 patients with median age 63 (IQR 51, 71) years, 63 patients (35.8%) were female and 31 patients (14.8%) had a history of atrial fibrillation. 165 patients (93.8%) had mitral repair, 18 (10.2%) had concomitant CABG, 22 (12.5%) had concomitant ablation procedure and 14 (8.0%) had concomitant tricuspid procedure. 114 patients (64.8%) were in NYHA Class I and 56 (31.8%) were in NYHA Class II. There was no operative mortality. Median % predicted peak VO2 (ppVO2) was 89 (74, 101), median ventilatory equivalent of carbon dioxide (VE/VCO2) was 28.0 (25.7, 31.0) l/min/l/min and median respiratory exchange ratio was 1.2 (1.1, 1.2). 73 patients (41.5%) had abnormal CPET (defined as ppVO2<85%). Median LVEF was 65 (60, 68) %, median LVESD was 35 (32, 38) mm and median LVGLS was 18.5 (16.6, 20.3) %. 45 patients (25.9%) had abnormal LVEF (defined as ≤ 60%), 11 patients (6.7%) had abnormal LVESD (defined as ≥45mm) and 35 patients (20.8%) had abnormal LVGLS (defined as <16%). At a median follow up of 10.2 (6.8, 13.2) years, there were 19 (10.8%) deaths. In the univariate analysis, age at surgery (HR 1.12, p<0.001), LVESD (HR 1.11, p=0.009), LVGLS (HR 1.11, p=0.013) and VE/VCO2 (HR 1.08, p=0.044) were associated with all cause mortality. Conclusion: A significant proportion of patients with no or mild symptoms exhibit echocardiographic evidence of LV impairment when having surgery for severe primary MR. CPET parameters such as VE/VCO2 and novel echocardiographic measurements such as LVGLS may predict risk of long term mortality and potentially inform timing of surgery in these patients.

Introduction: Among patients with cardiogenic shock (CS), high right atrial pressure (RAP) and low mean arterial pressure (MAP) are associated with in-hospital mortality. Pressure-adjusted heart rate (PAHR), defined as heart rate * RAP-to-MAP ratio (HR * [RAP/MAP]), integrates these parameters and has been used to identify cardiovascular dysfunction in critical illness. Higher PAHR values associate with higher surgical ICU mortality, but the prognostic significance of PAHR has not been assessed in cardiac intensive care unit (CICU) patients with CS. Hypothesis: We hypothesized that higher PAHR values are associated with higher risk of in-hospital mortality in patients with CS. Methods: The Critical Care Cardiology Trials Network (CCCTN) is a multinational registry of CICUs coordinated by the TIMI Study Group. Among CS admissions (2018-2023) undergoing invasive hemodynamic assessment within 24h of CICU admission, we calculated PAHR (in bpm) and assessed its relationship with in-hospital mortality. Patients on temporary mechanical circulatory support were excluded. Odds ratios were adjusted for age, sex, vasoactive-inotropic score (VIS), SCAI stage, and preceding cardiac arrest. Subgroup analyses stratifying by CS subtype were performed. Results: Among the 1411 CS admissions in the analysis cohort (mean age 61 years, 31% women), 18% had AMI-CS, 75% had HF-CS, and 7% had secondary CS. At the time of assessment (median 1.4h after CICU admission), 75% were on vasoactive support (median VIS 3.8). Median HR was 92 (Q1-Q3 77-109) bpm, RAP 15 (Q1-Q3 10-19) mmHg, MAP 75 (Q1-Q3 67-87) mmHg, and PAHR 17 (Q1-Q3 11-24) bpm. A stepwise gradient of higher in-hospital mortality with increasing PAHR values (p-trend <0.001; Fig ) was observed. In adjusted models, a higher PAHR was associated with higher in-hospital mortality (aOR per 10-bpm, 1.35 [95% CI, 1.15-1.58]), and had stronger prognostic associations with mortality than its individual hemodynamic components (Fig) . Conclusion: Higher PAHR is strongly associated with in-hospital mortality in CS patients. PAHR, a simple parameter which is readily calculable without needing a pulmonary artery catheter, may aid in identifying CS patients at higher risk of death.

Objectives: The aims of the study are to develop a prostate cancer risk prediction model that combines clinical and magnetic resonance imaging (MRI)–related findings and to assess the impact of adding Prostate Imaging-Reporting and Data System (PI-RADS) ≥3 lesions-level findings on its diagnostic performance. Methods: This 3-center retrospective study included prostate MRI examinations performed with clinical suspicion of clinically significant prostate cancer (csPCa) between 2018 and 2022. Pathological diagnosis within 1 year after the MRI was used to diagnose csPCa. Seven clinical, 3 patient-level MRI-related, and 4 lesion-level MRI-related findings were extracted. After feature selection, 2 logistic regression models with and without lesions-level findings were created using data from facility I and II (development cohort). The area under the receiver operating characteristic curve (AUC) between the 2 models was compared in the PI-RADS ≥3 population in the development cohort and Facility III (validation cohort) using the Delong test. Interfacility differences of the selected predictive variables were evaluated using the Kruskal-Wallis test or chi-squared test. Results: Selected lesion-level features included the peripheral zone involvement and apparent diffusion coefficient (ADC) values. The model with lesions-level findings had significantly higher AUC than the model without in 655 examinations in the development cohort (0.81 vs 0.79, respectively, P = 0.005), but not in 553 examinations in the validation cohort (0.77 vs 0.76, respectively). Large interfacility differences were seen in the ADC distribution (P < 0.001) and csPCa proportion in PI-RADS 3–5 (P < 0.001). Conclusions: Adding lesions-level findings improved the csPCa discrimination in the development but not the validation cohort. Interfacility differences impeded model generalization, including the distribution of reported ADC values and PI-RADS score-level csPCa proportion.

The hierarchical organization of the connective tissue, more specifically, the musculoskeletal soft tissue, has been extensively studied. With advancements in experimental methodology, investigation of the structure–function relationship has provided more insight into how the mechanical integrity of the tissue is created. Such information is essential in the linking the macroscopic loading environment of the tissue to the microscopic level of the tissue to be experienced by the cell. The flexibility and elastic modulus of gross connective tissue, the fascicle, the fiber and then the collagen molecule are compared based on the data available in the literature.

Abstract As patients with relapsed/refractory multiple myeloma (RRMM) continue to live longer, they might get exposed to most available drugs and drug classes during the disease course. For such late line RRMM or among patients without access to novel therapies, retreatment with a drug that the disease had previously been refractory to might be one option. In this retrospective study, we describe 315 patients with RRMM at our institution who were retreated with a drug that the disease had been previously refractory to. We found an overall response rate of 56.2% and a median progression-free survival (PFS) of 11 months with retreatment. Patients with a longer time on initial therapy with the index drug (&gt;28.4 months) had a superior PFS with retreatment (median PFS, 16.9 vs 8.1 months; P &lt; .001). Similarly, patients with a longer time gap between the initial line of therapy with index drug and retreatment with index drug (&gt;46.1 months) had better PFS with retreatment (28.2 vs 8.9 months; P = .016). In conclusion, retreatment with a previously refractory drug is a viable therapeutic option for RRMM, with the most significant benefit derived in disease demonstrating sensitivity to initial drug exposure and among those with a longer gap between initial drug exposure and retreatment.

Abstract The determination of the genetic subtypes of primary central nervous system lymphoma (PCNSL) and their relationship to differential chemoimmunotherapeutic response has not been established. There is a particular need for genomic biomarkers that identify patients with newly diagnosed PCNSL at high risk of early progression and death. We applied targeted next-generation sequencing for detection of recurrent single-nucleotide variants, copy number alterations, and zygosity abnormalities in diagnostic specimens from 78 patients with PCNSL treated with a standard methotrexate-based regimen, to identify prognostically significant molecular subgroups. All patients received induction immunochemotherapy, and 44 proceeded to dose-intensive consolidation. Genomic aberrations at 4 loci were associated with 91% of lymphoma progression events and all 15 deaths: (1) chromosome 6p copy-neutral loss of heterozygosity (CN-LOH) or focal homozygous deletion (HD) at 6p21.3, and mutations of tumor suppressor genes (2) BTG1, (3) ETV6, and (4) TP53. Cox regression multivariate analysis demonstrated a high risk of progression in patients with aberrations at these loci. Genomic aberrations at these loci were also associated with significantly shorter survival. Lower expression of HLA-DR was associated with 6p CN-LOH/6p21.3 HD and inferior prognosis. These genomic aberrations identify a high-risk molecular subgroup that may inform risk stratification in PCNSL. Further elucidation of the mechanisms of therapeutic resistance associated with the high-risk genetic phenotype is requisite to facilitate precision medicine and progress in therapy.

Abstract Aspiration-related syndromes comprise a broad spectrum of diseases affecting the airways and lung parenchyma resulting from inadvertent entry of oropharyngeal or gastric contents into the respiratory tract. The diagnosis can be challenging given lack of self-reported symptoms and unwitnessed or silent aspiration events. Aspiration is a common finding in healthy individuals suggesting that host defenses play a critical role in the pathophysiology. In the absence of strict criterion, a high index of suspicion is necessary based on recognition of established risk factors and identification of characteristic imaging findings. Conditions predisposing to altered levels of consciousness and neuromuscular weakness can lead to dysphagia, impaired cough reflux, and subsequent aspiration. The most salient feature on imaging is the anatomic location of the abnormalities, with the superior segments of the lower lobes and posterior segments of upper lobes involved in the recumbent position, and basilar segments of lower lobes in the upright position. Acute syndromes include pneumonia, pneumonitis, and foreign body aspiration. In the more indolent form of aspiration, bronchiectasis, diffuse bronchiolitis, and interstitial lung disease can develop. A detailed understanding of associated radiographic findings for these syndromes can help to implicate aspiration as the cause for imaging abnormalities and ultimately optimize patient management.

Abstract Background: Head and neck squamous cell carcinoma (HNSCC) is the sixth most common malignancy globally, and the vast majority of cases are treated with primary surgical resection and adjuvant therapy. Our group has pioneered the use of HNSCC circulating tumor DNA (ctDNA) in surgical effluent collected postoperatively from surgical drains (surgical drain fluid, SDF) as a novel proximal bioanalyte for measuring minimal residual disease after surgery. We now profile the immune cell composition of SDF compared to paired peripheral blood mononuclear cells (PBMCs), and correlate SDF immune cell profiles with clinical variables and oncologic outcomes in HNSCC. Method: SDF and peripheral venous blood were collected 24 hours postoperatively from 58 HNSCC patients, including 11 HPV (+) and 47 HPV (-) patients undergoing standard of care surgical resection, lymph node dissection, and adjuvant therapy. Freshly collected SDF cells and PBMCs were cryopreserved until profiling by multicolor flow cytometry for respective leukocyte compositions. Analyses were used to define the following viable CD45+ leukocyte subsets: total T cells, CD4 T-cells CD8 T-cells, Treg cells, B-cells, non- classical monocytes, classical monocytes, natural killer (NK) cells, classical dendritic cells (cDC), plasmacytoid DC (pDC), macrophages, and monocytic myeloid-derived suppressive cells (MDSCs). Immune cell percentages were correlated with clinical characteristics and cancer recurrence. Results: CD45+ leukocytes comprised &gt;99.5% of SDF cells, with very few EPCAM+ tumor cells (&lt; 10^-4). HPV status did not significantly affect SDF immune cell composition, and no significant differences were noted by tumor site (larynx, oral cavity, oropharynx), or extracapsular lymph node extension. Among 13 HPV (-) HNSCC patients with paired peripheral blood drawn concurrently, SDF had a higher proportion of B-cells(16.8% vs. 9%, p=0.044), NK cells(56% vs. 12%, P&lt;0.001), monocytes(14% vs. 1%, P&lt;0.001), and macrophages(3.1% vs. 0.46%, P&lt;0.001) compared to PBMCs, and a lower proportion of CD4+ T cells(1% vs. 24%, P&lt;0.001), CD8+ T cells(0.6% vs. 18%, P&lt;0.001), MDSCs(2.1% vs. 3.4%, P=0.029), and pDCs(0.1% vs. 0.2%, P=0.014). HPV (-) HNSCC patients that went on to recur (n=9) had a significantly higher proportions of SDF monocytes (total, classical, and non- classical) and CD56dimCD16+ NK cells (all P&lt;0.001) compared to non-recurrent patients (n=38). Patients who went on to recur also had a significantly lower proportion of SDF B-cells (P&lt;0.001), CD56bright NK cells(P=0.01), and macrophages (P=0.018) compared to non- recurrent cases. No significant differences were noted with respect to proportions of CD3+, CD4+, CD8+ T-cells, DC, and MDSC cells. Conclusion: SDF from HNSCC patients contains unique immune cell populations and may provide new insights into postoperative tumor immunity. Differences in SDF immune cell composition by oncologic outcome in patients that go on to recur, highlighting potential prognostic and predictive applications of SDF immune cell profiling for adjuvant therapy decision-making. Citation Format: Zhongping Xu, Noah Earland, Lucien Khalil, Lazar Vujanovic, Danny Azmi Elias, Riyue Bao, Jason J. Luke, Aadel A. Chaudhuri, Jose P. Zevallos. Immune cell composition in surgical drain fluid as a novel prognostic marker in head and neck squamous cell carcinoma [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr B031.

Abstract Purpose: Squamous cell carcinoma of the anus (SCCA) is primarily driven by human papillomavirus (HPV) infection. Up to 30% of patients experience recurrence, necessitating improved surveillance strategies. Liquid biopsies have shown promise as a tool in oncology. This study investigates the clinical performance of circulating tumor tissue modified viral (TTMV)- HPV DNA in the post-treatment surveillance of SCCA. Patients and methods: This central IRB-approved retrospective cohort study included 117 patients diagnosed with HPV-driven SCCA from seven U.S. centers who had ≥1 TTMV-HPV DNA tests (NavDx®, Naveris, Inc., Waltham, MA) performed between March 2020 and June 2024. TTMV-HPV DNA for HPV subtypes 16, 18, 31, 33, and 35 were analyzed using droplet digital PCR. The diagnostic accuracy of TTMV-HPV DNA was evaluated by comparing test results with clinical evidence of SCCA recurrence determined through anoscopy, radiology, and/or tissue biopsy. Recurrence is defined as either a positive biopsy or subsequent salvage therapy. Results: Patients were primarily female (73%) with a median age 63 years. Median follow-up after initial treatment was 19 months. Forty-seven patients (40%) had pretreatment TTMV-HPV DNA testing, with a baseline detectability of 85.1% (40/47, 95% CI: 74.9–95.3). Of these, 24 were re-tested within 3 months post-treatment and 18 had undetectable TTMV-HPV DNA (75%). Those patients whose scores became undetectable had significantly longer recurrence-free survival than those whose scores remained detectable (log-rank test, p=0.01). One hundred and four patients (89%) underwent post-treatment testing, of which 91 provided relevant data for the analysis. Of these 91 patients, 27 (29.7%) experienced recurrence. Post-treatment testing demonstrated a per- patient sensitivity of 85.7% (24/28, 95% CI: 72.8-98.7). Of four patients with a false negative test, only one had biopsy-confirmed recurrence, whereas the remaining recurrences were not biopsied prior to starting salvage treatment. The positive predictive value of a single positive test was 97.6% (40/41; 95% CI: 92.8–100.0). One patient remains in active follow-up. Of the true positive post-treatment tests, 58% (14/24) predicted recurrence before clinical detection, with a median lead time of 59 days (range: 10–536). There were 141 negative post-treatment tests across 66 patients. This yielded a per-test specificity and negative predictive value of 99.3% (136/137, 95% CI: 97.8-100.0) and 97.2% (136/140, 95% CI: 94.9-99.9), respectively. Indeterminate TTMV-HPV DNA tests were rare (5/268,1.9%). However, clinically indeterminate findings (CIFs) were common, with 141 post-treatment CIFs identified across 52/117 patients (44.4%). TTMV-HPV DNA testing was able to correctly predict recurrence status in 94.3% of CIF cases. Conclusion: TTMV-HPV DNA testing is a sensitive and specific surveillance method for detecting early recurrence of HPV-driven SCCA. Citation Format: Shane Lloyd, Rafi Kabarriti, James Jabalee, Tyler Slater, Corbin Jacobs, Sean Inocencio, Michael Rutenberg, Chance Matthiesen, Kasha Neff, Gene-Fu F Liu, Tiffany M Juarez, Catherine DV Fitz, Stanley Liauw. Plasma-based circulating tumor tissue modified viral (TTMV)-HPV DNA for detection of recurrent HPV-driven anal cancer [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr B018.