Citations

AbstractBackgroundWhile the list of fusion‐driven soft tissue neoplasms is expanding rapidly, their importance among cutaneous and superficial mesenchymal and adnexal neoplasms remains poorly understood. This challenge is especially evident in cases with ambiguous histopathology that are difficult to classify based on morphology.AimsOur goal was to investigate the benefits of next‐generation sequencing in diagnosing complex cutaneous neoplasms.Materials & MethodsDepartmental archives were searched for fusion‐driven cutaneous neoplasms. Slides were retrieved and clinical information including follow‐up was obtained.ResultsFifteen cases occurred in eight female and seven male patients, with a median age of 26 years (range: 1–83) at diagnosis. Tumors involved the extremities (9), scalp (5), and head and neck (1). Predominant features included myoepithelial (5), nested spindled with clear cytoplasm (2), atypical adnexal/squamoid (2), small round blue cell (2), cellular spindled (3), and fibrohistiocytic morphology (1). Most frequently encountered fusions involved EWSR1 (6) fused to ERG (1), FLI1 (1), CREB1 (2), CREM (1), PBX3 (1), followed by PLAG1 (4) with LIFR (2), TRPS1 (1) and CHCHD7. Additional fusions encountered were YAP1::NUTM1, EML4::ALK, SS18::SSX1 (2), and a novel fusion: ACTB::ZMIZ2. Integration of histologic features and molecular findings led to final diagnoses of primary cutaneous Ewing sarcoma (2), soft tissue myoepithelioma (4), cutaneous syncytial myoepithelioma (1), cutaneous adnexal carcinoma (1), porocarcinoma (1), inflammatory myofibroblastic tumor (1), synovial sarcoma (2), clear cell sarcoma (2), and angiomatoid fibrous histiocytoma (1).Discussion and conclusionOur results show that fusion testing can be a helpful diagnostic tool, especially in cases with unusual or uncommon morphology in superficial sites. Furthermore, it can allow for the identification of potential therapeutic targets in some instances.

This cross-sectional study estimates the number of average-risk colorectal cancer screening–eligible individuals in the US since the US Preventive Services Task Force updated its recommendations in 2021.

Purpose To report the clinical outcomes and reoperation rates of arthroscopic and endoscopic iliopsoas release at short‐term follow‐up after ipsilateral total hip arthroplasty (THA) at 2 separate medical institutions and to evaluate whether demographic and radiographic parameters are associated with postoperative patient‐reported outcomes (PROs). Methods Patients with iliopsoas tendinitis in the setting of prior THA who underwent arthroscopic iliopsoas fractional lengthening from 1988 to 2023 at 2 academic institutions were reviewed. Patients were included if they had 12 months of follow‐up and underwent evaluation of preoperative anterior acetabular component overhang, surgery satisfaction, postoperative subjective hip flexion strength and anterior groin pain improvement, modified Harris Hip Score, Single Assessment Numeric Evaluation score, Tegner activity scale score, visual analog scale (VAS) score, and revision hip arthroplasty. Results Sixty hips in 58 patients (19 male and 39 female patients) were followed up for a mean of 39.3 months (range, 12.0‐105.9 months) postoperatively. Of the patients, 77% reported feeling “much better” or “slightly better,” 75% reported improved anterior groin pain, and 60% reported improved subjective hip flexion strength. The surgery satisfaction rating was 7.2 ± 3.3 (scale of 0 to 10). The mean postoperative modified Harris Hip Score, VAS score for pain at rest, VAS score for pain with use, and Single Assessment Numeric Evaluation score were 73.9 ± 19.4, 1.3 ± 2.4, 3.8 ± 2.9, and 71.9 ± 21.9, respectively. Preoperative anterior acetabular component overhang was 3.3 ± 6.5 mm and did not significantly correlate with postoperative PROs ( P ≥ .45). The Tegner score improved from 2.5 ± 1.7 preoperatively to 2.9 ± 1.4 postoperatively ( P = .0253). Three patients underwent revision arthroplasty at a mean of 25.3 months (range, 11.6‐40.4 months) postoperatively, with an acetabular component revision rate of 3.3%. Conclusions Satisfactory outcomes and low revision arthroplasty rates were observed in patients undergoing arthroscopic iliopsoas lengthening after THA. There was no statistically significant relation between anterior acetabular component overhang and final PROs. Level of Evidence Level IV, therapeutic case series.

Purpose: The Manufacturer and User Facility Device Experience database contains anonymous, voluntary medical device reports. A review of device-related adverse events associated with Benign Prostatic Hyperplasia surgeries was completed. The objective was to evaluate the occurrence and contributing factors to clinically significant complications in a cohort of patients electing to undergo surgical intervention for Benign Prostatic Hyperplasia. Methods: The Manufacturer and User Facility Device Experience database was queried for “Aquablation, Greenlight Laser, Holmium Laser, Morcellator, Water Vapor Thermal Therapy, Loop Resection, and Prostatic Urethral Lift” from 2018 through 2021. A complication classification system (Level I–IV) based on the Clavien-Dindo system was used to categorize events. These events were then correlated with procedural technology malfunctions and classified as “device related” and “non-device related.” Chi squared analysis was performed to identify associations between procedural technology and complication classification distribution. Results: A total of 873 adverse events were identified. The adverse events were classified into level I (minimal harm) versus levels II–IV (clinically significant). Aquablation ( p < 0.017) and Water Vapor Thermal Therapy ( p < 0.012) were associated with a higher proportion of reports with Level II-IV complications compared with other procedure types. Level II-IV complications were not associated with a reported device related malfunction. Conclusions: Aquablation and water vapor thermal therapy demonstrated noteworthy clinically significant complications which were not driven by device-related malfunctions.

AbstractThe APOE4 allele is recognized as a significant genetic risk factor to Alzheimer's disease (AD) and influences longevity. Nonetheless, some APOE4 carriers exhibit resistance to AD even in advanced age. Humanin, a mitochondrial‐derived peptide comprising 24 amino acids, has variants linked to cognitive resilience and longevity. Our research uncovered a unique humanin variant, P3S, specifically enriched in centenarians with the APOE4 allele. Through in silico analyses and subsequent experimental validation, we demonstrated a strong affinity between humanin P3S and APOE4. Utilizing an APOE4‐centric mouse model of amyloidosis (APP/PS1/APOE4), we observed that humanin P3S significantly attenuated brain amyloid‐beta accumulation compared to the wild‐type humanin. Transcriptomic assessments of mice treated with humanin P3S highlighted its potential mechanism involving the enhancement of amyloid beta phagocytosis. Additionally, in vitro studies corroborated humanin P3S's efficacy in promoting amyloid‐beta clearance. Notably, in the temporal cortex of APOE4 carriers, humanin expression is correlated with genes associated with phagocytosis. Our findings suggest a role of the rare humanin variant P3S, especially prevalent among individuals of Ashkenazi descent, in mitigating amyloid beta pathology and facilitating phagocytosis in APOE4‐linked amyloidosis, underscoring its significance in longevity and cognitive health among APOE4 carriers.

Abstract Introduction: Pancreatic ductal adenocarcinoma (PDAC) is a major cancer killer with a low 5-year survival rate of 12%. Diagnosing PDAC at an early stage is one of the strongest predictors of long-term survival. Therefore, novel methods for early detection of PDAC must be explored. In this pilot study we aimed to compare the peripheral blood immune cell phenotypes in PDAC cases and cancer-free controls. Method: CyTOF (cytometry by time-of-flight) was used to evaluate peripheral blood mononuclear cells (PBMC) from newly diagnosed treatment naïve patients with PDAC and sex and age matched cancer-free controls using a 29-marker immune phenotyping panel. Multiple analysis approaches including dimensionality reduction using tSNE and clustering using Phenograph were used to evaluate the results. Immune subsets having differential abundance differences were verified by manual gating. Results: Twenty patients were included in this pilot study (15 PDAC cases; 5 Cancer-free controls). Among the 15 PDAC cases, 5 were early stage (Stage 1-2). Thirty-two unique immune cell clusters were identified using the Phenograph algorithm: 10 unique clusters with properties consistent with monocytes/macrophages, 9 CD4 T cell clusters, 6 CD8 T cell clusters and 4 NK cells clusters. When comparing the case and control groups we noted lower percentages of CD8+CD27+ T-cells in cases. This was further verified by manual gating that confirmed the distribution of CD8+CD27+ T-cells relative to all T-cells were decreased in PDAC patients. In addition, a 57% increase in naïve CD4 T cells was found in case samples compared to controls. A principal component analysis of the clustering results identified two unique clusters of immune profiles that emerged providing a potential peripheral blood immune cell signature that could stratify and differentiate PDAC cases from controls. A CD14+CD16+CD4LoCD38+CD45RO+ population of monocytes was the primary cell population driving this difference. Conclusion: This study provides early evidence to indicate that a distinct PBMC immune phenotype may differentiate PDAC patients from control subjects. Further analysis in larger sample sets is warranted for in-depth characterization and identification of unique immune based biomarkers for PDAC detection. Citation Format: Kevin D. Pavelko, Jose C. Villasboas, William R. Taylor, Karen A. Doering, John B. Kisiel, Shounak Majumder. Peripheral blood immune phenotypes in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2445.

Abstract Background Although CAR T-cell therapy has achieved remarkable response in patients (pts) with B-cell non-Hodgkin’s lymphoma (NHL), 20-30% of pts still have primary refractory disease (PD1), and another 30-40% relapse (PD2). We and others have shown that monocytes can modulate T-cell functions and impact clinical response to chemoimmunotherapy in NHL. Given that monocytes nadir and recovery kinetics differ from lymphocytes post lymphodepletion chemotherapy, we hypothesize that monocyte phenotype at peak CAR-T expansion and in the early month post CAR-T can modulate immune responses. Methods scRNAseq were performed on peripheral blood mononuclear cells of NHL pts prior to lymphodepletion chemotherapy (pre), at peak CAR-T expansion (peak), and one month following CAR-T (M1). Seurat v4.3.0 was used for unsupervised hierarchical clustering analysis. Lugano criteria was used to determine clinical responses which were categorized as CR (complete remission), PD1, or PD2. Results We analyzed 129,981 monocytes from 77 samples of 32 pts (16 CR, 4 PD1, 12 PD2) and 5 healthy controls. Unsupervised hierarchical clustering analysis identified 13 monocyte clusters: 4 classical monocyte (CM) clusters with transcriptome profiles for enriched signaling in IL-6, TGFβ, EMT, and p53; 2 intermediate monocyte (IM) clusters enriched for IL-1 or CD38 signaling; 2 non-classical monocytes (NM), one with increased CD36 expression; 3 monocytic MDSC clusters with enrichment of TGFβ, SIRPα, and HIF1α signaling; and 2 lymphoma-associated monocytes, expressing CD163 or CD169. At Pre and Peak, the distribution of the monocyte clusters was similar in pts with CR, PD2, or PD1, with only a slight decrease in the percent of NM in the PD2 group at Pre and slight increase of CD36 NM in PD1 at Peak. Compared to Pre, all pts had increased percent of CD36 NM and IL-1 IM at Peak. Interestingly, while the distribution of monocyte clusters was similar at Pre and Peak across clinical responses, GSEA showed that monocytes in CR pts, compared to PD1 and PD2, had gene expression enrichment of MYC target V2 pathway at Pre and TGFβ pathway at Peak. At M1, pts in PD1 had increased percent of p53 and TGFβ CM and decreased percent of NM. In contrast, pts with CR had decreased percent of IL-6 CM, p53 CM, TGFβ CM, IL-1 IM and increased percent of NM. Notably, as pts with CR and PD2 may appear similar clinically at M1, pts with PD2, compared to CR, have increased IL-6 CM, IL-1 IM, and decreased NM. In addition, GSEA showed that PD2 pts had increased IFNα response. Our results demonstrate that monocyte phenotype differences at Pre and Peak could be associated with CAR-T clinical response, and that persistent inflammatory monocyte signaling at M1 in pts with clinical response is associated with relapse. These data suggest a role for development of monocyte biomarkers to predict response and therapeutic targeting. Citation Format: Andre de Menezes Silva Corraes, Panwen Wang, Radhika Bansal, Henan Zhang, Zuoyi Shao, Kevin Regan, Eider Moreno Cortes, Arushi Khurana, Nora Bennani, Yucai Wang, Paul Hampel, Jonas Paludo, Patrick Johnston, Hemant Murthy, Madiha Iqbal, Stephen Ansell, Javier Munoz, Allison Rosenthal, Mohamed Kharfan-Dabaja, Januario Castro, Saad Kenderian, Haidong Dong, Ying Li, Yi Lin. Monocyte transcriptome profiles associated with clinical response in patients with B-cell non-Hodgkin’s lymphoma receiving CD19-directed CAR-T therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4001.

Abstract Background: Advanced prostate cancer is defined as metastatic hormone-sensitive prostate cancer (mHSPC) or castration-resistant prostate cancer (CRPC). Newer and aggressive treatments are leading to increasing lifespans in this population. As such, studying quality of life could have a large impact on the survivorship experience. An important component of quality of life is financial toxicity, defined as the financial burden and distress that can arise for patients and their families because of cancer treatment. Objectives: To understand the prevalence and predictors of financial toxicity in advanced prostate cancer. Methods: IRONMAN (International Registry of Men with Advanced Prostate Cancer) is a prospective cohort of patients with newly diagnosed mHSPC or CRPC enrolling in 15 countries. Financial toxicity was collected using the EORTC QLQ-C30 (“has your physical condition or medical treatment caused you financial difficulties?”) at enrollment and every three months thereafter. For this analysis, we studied 997 patients cared for at 37 US sites enrolled from 7/2017 to 7/2023. We examined baseline and longitudinal reports of financial toxicity across clinical and demographic factors: age at enrollment, race and ethnicity, disease state, marital status, education, employment, military status, and type of health center. We conducted adjusted risk difference analysis and multivariable regression modeling to identify predictors of financial toxicity using a generalized estimating equations approach to calculate odds ratios (OR and 95% confidence intervals, CI). Results: At enrollment, 125 (13%) patients reported experiencing “quite a bit” or “very much” financial toxicity. 21% of Black patients experienced toxicity compared to 10% of White patients. Even after incorporating all other predictors, Black patients experienced 5% (95% CI: 0, 11) greater toxicity than White patients. Independently of other predictors, patients &gt;75 experienced 11% (CI: -17, -4) lower toxicity compared to those &lt;65 years (while patients in the 65-74 group experienced 6% less, CI: -12, 1). Toxicity was 6% greater in patients with mHSPC (CI: 2, 10) than in patients with CRPC, and disabled or unemployed patients were at substantially higher risk. In the multivariable longitudinal analyses, older age (&gt; 75) remained associated with significantly lower odds for financial toxicity (OR: 0.30, 0.15-0.61) while mHSPC (OR: 1.91, 1.14-3.20) and being unemployed (OR: 2.69, 1.03-6.99) or disabled (OR: 5.14, 2.29-11.6) were associated with higher odds. Conclusions: Financial toxicity is prevalent in advanced prostate cancer, especially in patients who are Black, younger than 75, diagnosed with mHSPC, or unemployed/disabled. These results may inform identification of patients at high risk for financial toxicity to support delivery of patient-situation-informed care by clinicians and targeted aid for patients at highest risk. Citation Format: Isani Singh, Bailey Vaselkiv, Emily Rencsok, Karen Autio, Deborah Enting, Alicia Morgans, Joel Nowak, Kevin Kensler, David Nanus, Robert Dreicer, Brian Lewis, Oliver Sartor, Elisabeth Heath, Phillip Kantoff, Deborah Kaye, Daniel George, Lorelei Mucci. Financial toxicity among patients with advanced prostate cancer in the United States [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3410.