Miranda Lin

Immune checkpoint inhibitors (ICIs) have become an increasingly prominent therapeutic option in the management of a variety of cancers. As their clinical use expands, so too should our understanding of immune-related adverse events (irAEs) associated with these agents. By enhancing immune activation, ICIs can cause off-target inflammation in various tissues, including endocrine. We present a case illustrating a rare but life-threatening manifestation of ICI toxicity: simultaneous severe diabetes mellitus and thyrotoxicosis after just a single dose of ICI. This case highlights the importance of prompt recognition and timely intervention of acute, life-threatening endocrine irAEs. We discuss the pathophysiology, management, and clinical course of ICI-induced diabetes mellitus and thyroid disease, with brief discussion of endocrine irAEs as a surrogate of therapeutic efficacy.

Purpose:Pancreatic ductal adenocarcinoma (PDAC) frequently recurs after neoadjuvant therapy (NT) and curative-intent resection. Although major pathologic response predicts favorable outcomes, most patients achieve only minor response with a heterogeneous recurrence risk. We asked whether the spatial organization of residual PDAC encodes clinically relevant biology beyond residual tumor burden. Experimental Design:In a retrospective cohort of 203 patients with resected PDAC treated with NT and restricted to minor pathologic response, routine hematoxylin and eosin (H&E) whole-slide images were segmented into cancer and stroma using an artificial intelligence–enabled pipeline. Spatial composition (patch density, edge density) and configuration (compactness/complexity, intermixing) were quantified and tested for associations with disease-free survival (DFS) using multivariable models adjusted for standard clinicopathologic factors. Results:Shorter DFS was associated with a fragmented, interface-rich tumor–stroma ecology featuring higher edge density and diversity and reduced homotypic aggregation, independent of clinicopathologic variables. Two spatial risk models were independently prognostic: (i) cancer mean shape index plus stromal shape index variability [adjusted hazard ratio (HR), 1.71; P = 0.003] and (ii) mean stromal patch area plus edge density (adjusted HR, 2.19; P = 0.002). Both models stratified outcomes in which pathologic response grading and residual cancer area did not. High-risk configurations were further associated with reduced intratumoral tumor-infiltrating lymphocyte (TIL) density and infiltration ratio, with relative TIL accumulation at the cancer periphery and within the stroma, consistent with an immune-excluded phenotype. Conclusions:Residual cancer–stroma topology quantified from standard H&E slides yields independent prognostic signals after NT in PDAC, provides a cellular immune correlate for spatial risk, and motivates prospective validation and spatially informed adjuvant strategies.

Cross-classification of patients by RPTR and Cox spatial risk models.

Performance of the PathExplore PDAC model for tissue segmentation.

Correlation between spatial features and histologic grade.

GATA6 Immunohistochemical Results.

Correlation between spatial features and pathologic nodal status.

Correlation between spatial features and pathologic tumor score.

Cohort-level distributions of spatial composition and diversity features.

Cohort-level distributions of spatial configuration features.