Faculty Bibliography

Appendiceal tumors are uncommon, and their coexistence as collision tumors is exceedingly rare, with fewer than 20 cases reported to date. The objective is to report a multi-center case series and literature review of appendiceal collision tumors, providing a comprehensive summary of clinicopathological features and outcomes. Electronic records from five tertiary centers (2016-2024) were searched. Cases with appendiceal collision tumors composed of a neuroendocrine tumor (NET) and a second component of low- or high-grade appendiceal mucinous neoplasm (LAMN/HAMN) or adenocarcinoma were included. Additional cases with the same diagnostic combinations were identified through a PubMed literature search since 2000. Clinical, pathologic, and survival data were collected and analyzed. Thirty-three cases were identified, including 17 multi-institutional and 16 literature-derived cases, with an estimated incidence of 0.11% among appendectomies. Most tumors consisted of localized NET and LAMN. Gastrointestinal (GI) symptoms were present in 62.5-65.6% of cases, and tumors were identified by imaging in 53.1-75.0%. Outcome tracks the higher-stage and grade component. Patients with localized tumors had excellent outcomes (2-year progression-free survival [PFS] and overall survival [OS]: 100%). In contrast, cases with metastatic LAMN/HAMN had 2-year PFS 66.7% and OS 100%, while those with metastatic adenocarcinoma had 2-year PFS 0% and OS 66.7%. This study represents the largest series and literature review of appendiceal collision tumors to date. These rare tumors most often consist of localized NET and LAMN, typically present with GI symptoms, are often detected by imaging. The prognosis is dictated by the component of higher stage and grade.

Neoadjuvant therapy (NAT) is increasingly used for pancreatic ductal adenocarcinoma (PDAC); yet most patients only achieve partial response. Pathological treatment response grading focuses on assessing residual tumor burden, often overlooking changes in tumor microenvironment (TME). To address this gap, we compared tumor cells and TME of 13 NAT-naïve and 23 post-NAT PDACs using integrated spatial pathomics and transcriptomics, with validation in an independent single-cell spatial dataset. NAT significantly reduced tumor burden (14.7%-6.2%, p = 0.004), but systemic comparison of 13 cytomorphometric features of tumor cells alone did not reliably distinguish between naïve and NAT cases. In contrast, NAT profoundly remodeled TME by increasing cancer-associated fibroblast (CAF) and CD8⁺ T cell densities, promoting CD8⁺ T cell-tumor cell proximity and fibrosis, reducing tumor-associated neutrophils, and redistributing tertiary lymphoid structures (TLSs). Spatial transcriptomics shows NAT induced apoptosis, DNA-damage response, and AGC-kinase (S_TK_X) signaling in tumor cells, and upregulated complement pathway, p53 signaling, and cellular senescence program in TME. Cross-platform single-cell spatial analysis revealed decreased regulatory T cells (Treg) and a shift from myofibroblastic (mCAF) to inflammatory CAF (iCAF). Importantly, post-NAT patients with more fibrosis had longer overall survival (p = 0.02), and higher B-cell density showed a favorable trend (p = 0.06). Together, these results suggest that beyond tumor debulking, NAT induces a coordinated TME remodeling characterized by fibroblast reprogramming, matrix fibrosis, and immune spatial reorganization. Incorporating assessment of NAT-induced stromal and immune changes into TRG may improve prognostication and guide more precise therapy in post-NAT PDAC.

Neoadjuvant therapy (NAT) is the standard of care for borderline-resectable and locally advanced pancreatic ductal adenocarcinoma (PDAC). It can be used to treat resectable PDAC. This study aimed to investigate how NAT remodels the tumor immune microenvironment (TIME) and whether this remodeling translates into survival benefits. We performed spatial and digital pathology analysis of 27 upfront resection patients (naïve group) and 39 age-, gender-, and stage-matched patients who had surgery after NAT (NAT group). AI-assisted digital pathology was used to annotate cancer cells and CD8 + T lymphocytes. Spatial correlation between CD8 + T lymphocytes and cancer cells for each case was assessed using spatial point pattern analysis, followed by generalized linear modeling (GLM) of quadrat counts of CD8 + T cells, with the quadrat counts of cancer cells as the independent variable. The regression coefficient was used to quantify the strength of their spatial correlation and then further assessed for association with patient survival. The analyses showed that the NAT group, compared with the naïve group, had increased spatial correlation of CD8 + T cells with cancer cells, suggesting enhanced effector T cell-cancer cell engagement in the NAT patients. Additionally, patients with a higher degree of spatial correlation between the two cells showed improved after-surgery survival. Through a new methodological framework that takes advantage of AI-assisted digital pathology and spatial point pattern analysis, our study has successfully captured the subtle effects of NAT-induced TIME remodeling and assessed its impact on prognosis of PDAC patients.

BACKGROUND AND AIMS/OBJECTIVE:Liver biopsy is the gold standard for assessing fibrosis in cirrhotic livers, yet cirrhosis is spatially heterogeneous and continuously remodels. This study evaluates a novel phenotypic digital pathology platform for continuous fibrosis severity quantification and sensitivity to sampling variability. APPROACH AND RESULTS/RESULTS:Five needle biopsies were collected from 20 HCV-cirrhotic livers during transplantation. Histological staging used the Laennec (4A-4C) and Beijing (progressive, regressive, indeterminate) systems. Collagen proportionate area (CPA) was measured via computerised morphometry. The FibroNest platform analysed high-resolution, single-fibre images to extract 336 parameters, generating a continuous fibrosis severity score (Ph-FCS) and tailored scores for Laennec (Ph-FCS(L)) and Beijing (Ph-FCS(B)) systems. A comparative MASLD cohort (n = 73, NASH-CRN stages) was also included. The range of the Ph-FCS was broader to cover the cirrhosis spectrum (6.44 units) than from F0 to F3 (5.39 units). Ph-FCS was less affected by biopsy variability (16.7% ± 1.3%) compared to CPA (47.3% ± 4.5%). Ph-FCS(L) and Ph-FCS(B) demonstrated moderate concordance with the Laennec and Beijing stages. Their ability to classify patients into Laennec and Beijing stages was limited (0.610 < AUROCS < 0.789). At best, Ph-FCS(L) and Ph-FCS(B) distinguished stages 4A from 4C and P from R with AUROCs of 0.747(95% CI: 0.611-0.879) and 0.798 (95% CI: 0.645-0.929). CONCLUSIONS:Phenotypic digital pathology biomarkers provide robust, continuous measures of fibrosis severity and activity. They enhance traditional staging systems by offering improved resolution and reduced sensitivity to biopsy variability, with potential value in cirrhosis sub-staging and clinical decision-making.

Neoadjuvant therapy (NAT) is increasingly being used for pancreatic ductal adenocarcinoma (PDAC). This study investigates how NAT differentially impacts PDAC's carcinoma cells and the tumor microenvironment (TME). Spatial transcriptomics was used to compare gene expression profiles in carcinoma cells and the TME of 23 NAT-treated versus 13 NAT-naïve PDACs. Findings were validated by single-nucleus RNA sequencing (snRNA-seq) analysis. NAT induces apoptosis and inhibits proliferation of carcinoma cells and coordinately upregulates multiple complement genes (C1R, C1S, C3, C4B and C7) within the TME. Higher TME complement expression following NAT is associated with increased immunomodulatory and neurotrophic cancer-associated fibroblasts (CAFs); more CD4⁺ T cells; reduced immune exhaustion gene expression, and improved overall survival. snRNA-seq analysis demonstrates C3 complement is mainly upregulated in CAFs. These findings suggest that local complement dynamics could serve as a novel biomarker for prognosis, evaluating treatment response, and guiding therapeutic strategies in NAT-treated PDAC patients.

PURPOSE/UNASSIGNED:swine model. METHODS/UNASSIGNED: = 6). Bowel was inspected for gross and microscopic damage, and treatment zones were measured. A ray-tracing simulation estimated the percentage of therapeutic beam path blockage by bowel in each scenario. RESULTS/UNASSIGNED: > 0.3 for bowel 1 cm and 2 cm above the phantom). Gas-filled bowel was estimated to have blocked 49.6%, 35.0%, and 27.3% of the therapeutic beam at 0, 1, and 2 cm, respectively. CONCLUSION/UNASSIGNED:survival model appears indicated.

BACKGROUND/UNASSIGNED:Neoadjuvant therapy (NAT) is increasingly being used for pancreatic ductal adenocarcinoma (PDAC) treatment. However, its specific effects on carcinoma cells and the tumor microenvironment (TME) are not fully understood. This study aims to investigate how NAT differentially impacts PDAC's carcinoma cells and TME. METHODS/UNASSIGNED:Spatial transcriptomics was used to compare gene expression profiles in carcinoma cells and the TME between 23 NAT-treated and 13 NAT-naïve PDAC patients, correlating with their clinicopathologic features. Analysis of an online single-nucleus RNA sequencing (snRNA-seq) dataset was performed for validation of the specific cell types responsible for NAT-induced gene expression alterations. RESULTS/UNASSIGNED:T cells, monocytes, and mast cells; and reduced immune exhaustion gene expression. snRNA-seq analysis demonstrates C3 complement was specifically upregulated in CAFs but not in other stroma cell types. CONCLUSIONS/UNASSIGNED:NAT can enhance complement production and signaling within the TME, which is associated with reduced immunosuppression in PDAC. These findings suggest that local complement dynamics could serve as a novel biomarker for prognosis, evaluating treatment response and resistance, and guiding therapeutic strategies in NAT-treated PDAC patients.

PURPOSE/OBJECTIVE:This study was designed to evaluate the feasibility and safety of histotripsy subcutaneous (SQ) fat treatment in an in-vivo porcine model, and evaluate evolution of the treated volume on MRI and pathology. METHODS/MATERIALS/METHODS:10 histotripsy SQ fat treatments were completed in 5 swine, divided into four groups based on pre-determined survival: day 0 (n = 4), day 7 (n = 2), day 28 (n = 2), and day 56 (n = 2). A 4.0 × 4.0x2.0 cm ovoid treatment was created in the fat pad of the posterior thorax. MRI of survived animals were obtained on day 7 (n = 6), day 28 (n = 4), and day 56 (n = 2), and reviewed for size and imaging characteristics. Technical success was defined as the creation of a treatment zone in the targeted SQ fat. Skin firmness and indentation were qualitatively scored. RESULTS:(± 1.2) by day 56 (92% overall decrease). Mean firmness and indentation scores showed no change from baseline at all time points, with no overlying skin injury. CONCLUSION/CONCLUSIONS:Histotripsy safely and effectively treated SQ fat of an in-vivo porcine model, with volume reduction over time.

Liver injury is a common manifestation of coronavirus disease 2019 (COVID-19), with most injuries manifesting as transient mild hepatocellular injury. Cholestatic injury occurs less commonly and is typically mild. Severe cholestatic injury is rare, with only 4 cases reported in the literature. We present a 70-year-old woman with no known liver disease who presented with severe COVID-19 and developed severe cholestatic hepatitis. A liver biopsy was performed demonstrating bile duct injury, uncommonly reported in patients with COVID-19. This complication needs greater awareness because it has been known to cause progressive liver disease requiring transplantation.