Citations

Abstract Introduction Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest cancers. While total neoadjuvant therapy (TNT) has improved outcomes, recurrence rates remain high. Major pathologic response after TNT is prognostic of better survival, but is rarely achieved. Current pathologic systems primarily consider residual tumor percentage, nodal status, and perineural invasion but overlook spatial organization within the tumor microenvironment (TME). We aimed to evaluate spatial features of the TME to identify biologically and clinically relevant patterns of TME conformation and configuration after TNT and surgical resection of PDAC. Methods We retrospectively analyzed patients with PDAC treated with TNT followed by surgery at Mayo Clinic (2010-2022) with partial or no response per College of American Pathologists (CAP) criteria. Hematoxylin and eosin-stained whole slide images (WSIs) were processed using PathExplore™ PDAC (v1.0) to quantify spatial TME features. These were correlated with disease-free survival (DFS). Results A total of 203 patients were included: 47.3% female, median age 66.5 years. All received TNT; 73.4% had neoadjuvant chemotherapy followed by chemoradiation. Surgical procedures included pancreaticoduodenectomy (62.1%), distal pancreatectomy (22.2%), and total pancreatectomy (15.8%). CAP-defined response was partial in 82.1% and absent in 17.9%. As expected, pathologic T stage (p=0.001), N stage (p=0.002), lymphovascular invasion (p=0.048), and R2 resection (p=0.007) were significantly associated with DFS. However, CAP response category (p=0.053), residual cancer area (p=0.47), and cancer-to-stroma ratio (p=0.25) were not. We analyzed 297 WSIs from 203 patients. Of 31 spatial features evaluated, 5 were associated with DFS (p<0.20). Recursive partitioning using ln(mean cancer shape index [CSI]) <1.775 and ln(SD of stroma shape index [SSI]) >0.651 identified a high-risk group (n=63) with median DFS of 7.23 months (95% CI: 5.19–9.63), compared to 11.57 months in the low-risk group (95% CI: 9.24–17.92) (HR=1.82; 95% CI: 1.31–2.52; p=0.0003). This remained significant after adjusting for T and N stage (HR=1.75; 95% CI: 1.17–2.63; p=0.007). An alternate prognostic index derived via backwards elimination, calculated using 0.2701(mean stromal area) + 0.3905(edge density), also stratified patients. High-risk patients (n=51) had a significantly shorter (p<0.001) DFS (6.2 months) than those in the low-risk category (20.0 months). This significant difference holds in a multivariable analysis controlling for pathologic stage, N stage, and resection margins (HR=1.94, 95% CI: 1.21-3.10, p=0.006). Discussion Current assessment of residual PDAC after TNT is limited by subjective grading and lack of spatial context. Using Tumor Landscape Analysis, we identified high-risk spatial features of the TME that independently predict recurrence. These findings support a novel spatially-informed framework for risk stratification in resected PDAC with residual disease. Citation Format: Miranda Lin, Luis Cisneros, Merih D. Toruner, Andrea Maraone, Paul Dizona, Qian Shi, Martin E. Fernandez-Zapico, Ryan M. Carr. Spatial features of the tumor microenvironment predict recurrence risk in resected pancreatic ductal adenocarcinoma after total neoadjuvant therapy [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_3):Abstract nr A051.

Abstract Pancreatic ductal adenocarcinoma (PDAC), the most common histological subtype of pancreatic cancer, is a devastating disease predicted to be the second leading cause of cancer deaths by 2040. Despite extensive molecular characterization, therapeutic targeting of this disease remains largely unsuccessful. Thus, an increased understanding of the mechanisms driving malignant features of PDAC is critical for the development of new therapeutic strategies. Of these, cancer cell survival is a central malignant event in PDAC contributing to disease initiation, progression, and response to therapy. To date, the majority of cell survival mechanisms associated with PDAC biology has highlighted the role of cytoplasmic and extracellular factors, making the role of nuclear elements understudied. Our preliminary data has demonstrated evidence of a novel mechanism regulating nuclear envelope stability, a key process contributing to cell survival. Work from our lab has shown that oncogenic KRAS, the major genetic driver of PDAC and present in ∼40% of cases, is sufficient to reduce the incidence of spontaneous nuclear envelope rupture, a measure of nuclear envelope stability. Using laser-induced nuclear envelope rupture revealed the presence of oncogenic KRAS decreases the extent of ruptures, suggesting an axis downstream of oncogenic KRAS is key for regulation of nuclear stability. Analysis of nuclear lamins, key intermediate filaments providing structure to the nuclear envelope, revealed only A-type lamins, not B-type, are associated with overall PDAC survival and enrich at the nuclear periphery downstream of oncogenic KRAS. Furthermore, BioID protein-protein interaction assays to examine the oncogenic KRAS-induced effects on nuclear repair proteins identified an increase in interaction between Lamin A and Emerin. Knock-down of either protein results in increases in nuclear envelope spontaneous ruptures. Together our findings provide a novel oncogenic KRAS-Lamin A-Emerin axis controlling the nuclear stability in PDAC, which can serve as a new therapeutic avenue to improve PDAC treatment outcomes. Citation Format: Kayla C. LaRue-Nolan, Ashley N. Sigafoos, Luis F. Flores, Kyle J . Roux, Martin E. Fernandez-Zapico. The role of Lamin A in pancreatic cancer nuclear envelope stability [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_3):Abstract nr A059.

ABSTRACT Cellular senescence is an irreversible form of cell‐cycle arrest caused by excessive stress or damage. While various biomarkers of cellular senescence have been proposed, there are currently no universal, stand‐alone indicators of this condition. The field largely relies on the combined detection of multiple biomarkers to differentiate senescent cells from non‐senescent cells. Here we introduce a new approach: unbiased cell culture selections to identify senescent cell‐specific folded DNA aptamers from vast libraries of trillions of random 80‐mer DNAs. Senescent mouse adult fibroblasts and their non‐senescent counterparts were employed for selection. We demonstrate aptamer specificity for senescent mouse cells in culture, identify a form of fibronectin as the molecular target of two selected aptamers, show increased aptamer staining in naturally aged mouse tissues, and demonstrate decreased aptamer staining when p16 expressing cells are removed in a transgenic INK‐ATTAC mouse model. This work demonstrates the value of unbiased cell‐based selections to identify new senescence‐specific DNA reagents.

OBJECTIVE The Centers for Medicare & Medicaid Services (CMS) requires a low C-peptide level for insulin pump coverage unless the individual is β-cell autoantibody positive, which precludes coverage of automated insulin delivery (AID) systems for many people with type 2 diabetes. RESEARCH DESIGN AND METHODS In the Randomized Trial Evaluating the Efficacy and Safety of Control-IQ+ Technology in Adults With Type 2 Diabetes Using Basal-Bolus Insulin Therapy study evaluating the t:slim X2 insulin pump with Control-IQ+ technology, adults with insulin-treated type 2 diabetes were categorized into high C-peptide (n = 195) and low C-peptide (n = 59) groups based on CMS criteria. RESULTS In the AID group, mean HbA1c decreased from baseline by 0.8%, which was significantly greater than in the control group with both high (P < 0.001) and low (P = 0.02) C-peptide levels. Results were similar in participants ≥65 years old. CONCLUSIONS The benefit of AID is present with high and low C-peptide levels. Thus, requiring a low C-peptide level as a prerequisite for AID therapy is not warranted.

Importance Multiparametric magnetic resonance imaging (MRI), with or without prostate biopsy, has become the standard of care for diagnosing clinically significant prostate cancer. Resource capacity limits widespread adoption. Biparametric MRI, which omits the gadolinium contrast sequence, is a shorter and cheaper alternative offering time-saving capacity gains for health systems globally. Objective To assess whether biparametric MRI is noninferior to multiparametric MRI for diagnosis of clinically significant prostate cancer. Design, Setting, and Participants A prospective, multicenter, within-patient, noninferiority trial of biopsy-naive men from 22 centers (12 countries) with clinical suspicion of prostate cancer (elevated prostate-specific antigen [PSA] level and/or abnormal digital rectal examination findings) from April 2022 to September 2023, with the last follow-up conducted on December 3, 2024. Interventions Participants underwent multiparametric MRI, comprising T2-weighted, diffusion-weighted, and dynamic contrast–enhanced (DCE) sequences. Radiologists reported abbreviated biparametric MRI first (T2-weighted and diffusion-weighted), blinded to the DCE sequence. After unblinding, radiologists reported the full multiparametric MRI. Patients underwent a targeted biopsy with or without systematic biopsy if either biparametric MRI or multiparametric MRI was suggestive of clinically significant prostate cancer. Main outcomes and measures The primary outcome was the proportion of men with clinically significant prostate cancer. Secondary outcomes included the proportion of men with clinically insignificant cancer. The noninferiority margin was 5%. Results Of 555 men recruited, 490 were included for primary outcome analysis. Median age was 65 (IQR, 59-70) years and median PSA level was 5.6 (IQR, 4.4-8.0) ng/mL. The proportion of patients with abnormal digital rectal examination findings was 12.7%. Biparametric MRI was noninferior to multiparametric MRI, detecting clinically significant prostate cancer in 143 of 490 men (29.2%), compared with 145 of 490 men (29.6%) (difference, −0.4 [95% CI, −1.2 to 0.4] percentage points; P = .50). Biparametric MRI detected clinically insignificant cancer in 45 of 490 men (9.2%), compared with 47 of 490 men (9.6%) with the use of multiparametric MRI (difference, −0.4 [95% CI, −1.2 to 0.4] percentage points). Central quality control demonstrated that 99% of scans were of adequate diagnostic quality. Conclusion and relevance In men with suspected prostate cancer, provided image quality is adequate, an abbreviated biparametric MRI scan, with or without targeted biopsy, could become the new standard of care for prostate cancer diagnosis. With approximately 4 million prostate MRIs performed globally annually, adopting biparametric MRI could substantially increase scanner throughput and reduce costs worldwide. Trial registration ClinicalTrials.gov Identifier: NCT04571840

OBJECTIVE Open resective surgery (ORS) has become the standard of care for focal drug-resistant epilepsy (DRE). However, minimally invasive surgical alternatives, such as laser interstitial thermal therapy (LITT), have also been shown to be safe and effective. A meta-analysis comparing both treatments is warranted to assess the benefits of each modality for focal DRE. METHODS A literature search was conducted until March 14, 2024, to identify studies comparing LITT and ORS in patients with DRE. The primary outcomes included seizure freedom (SF), length of hospital stay (LHS), and complication rate (CR). Subgroup analyses were performed based on age, epilepsy etiology, and propensity score–matched (PSM) studies. RESULTS Of 558 articles, 15 cohort studies met the authors’ inclusion criteria, encompassing 3873 patients for analysis. The rate of SF in the LITT group was 52.5% (95% CI 0.453–0.597, I 2 = 47.4%) and 67.1% (95% CI 0.602–0.739, I 2 = 57.4%) for the ORS group. LITT showed a significantly lower rate of SF compared to ORS (risk ratio [RR] 0.78, 95% CI 0.70–0.88, p ≤ 0.0001). However, when PSM studies (RR 0.85, 95% CI 0.63–1.15, p = 0.30) and studies on patients with temporal lobe epilepsy (TLE) (RR 0.88, 95% CI 0.67–1.14, p = 0.34) were analyzed, the SF rates were similar. Patients who underwent LITT had a significantly shorter LHS (mean difference 2.95 days, 95% CI 1.12–4.78, p < 0.00001), lower CR (RR 0.54, 95% CI 0.37–0.79, p < 0.002, I 2 = 32%), lower rate of ischemic stroke (RR 0.15, 95% CI 0.04–0.65, p = 0.01), and lower rate of permanent neurological deficits (RR 0.13, 95% CI 0.05–0.36, p < 0.0001). CONCLUSIONS Across unmatched studies evaluating focal DRE, ORS showed a higher rate of SF. However, pooled matched-cohort analyses showed no difference between interventions in achieving SF, a trend also noted in the authors’ PSM TLE sample. LITT, however, offered significantly shorter LHS and lower CRs. Future prospective studies should match patient populations to control for confounding factors and assess key outcomes, such as postoperative neurocognitive follow-up and quality of life measurements, in order to fully evaluate the risks and benefits of each approach.

Abstract Active learning strategies enhance medical education by fostering self‐directed learning, communication, and problem‐solving skills. The paper puzzle, a game‐based learning approach, provides an engaging way to reinforce anatomical knowledge and promote collaboration. This study assessed its impact on student performance and perceptions in clinical anatomy, comparing it to PowerPoint‐based imaging reviews and evaluating the role of Near Peer Teachers (NPTs). A prospective, longitudinal, quasi‐experimental study with a mixed‐methods approach was conducted on first‐year medical students enrolled in the Human Anatomy course. Surveys using a Likert scale assessed student and NPT perceptions, while focus groups and interviews provided qualitative insights. Thematic analysis identified key themes related to engagement, knowledge reinforcement, and effectiveness. A total of 907 medical students and 30 NPTs completed a survey, while 75 students and 10 NPTs participated in the qualitative phase. Students perceived the paper puzzle as an engaging and interactive review tool that reduced stress, increased involvement, and enhanced knowledge retrieval through collaboration and a structured gameplay loop. They also valued the emotional impact on learning. NPTs reported benefits for student motivation and teamwork but noted that time constraints limited content coverage. The activity's effectiveness was highly dependent on the NPT's facilitation, emphasizing the need for structured implementation. Findings suggested that game‐based learning strategies like the paper puzzle can improve motivation, teamwork, and content retrieving in anatomy education when carefully designed and effectively executed by NPTs.