Scalable topic modelling decodes spatial tissue architecture for large-scale multiplexed imaging analysis.

Recent progress in multiplexed tissue imaging is deepening our understanding of tumor microenvironments related to treatment response and disease progression. However, analyzing whole-slide images with millions of cells remains computationally challenging, and few methods provide a principled approach for integrative analysis across images. Here, we introduce SpatialTopic, a spatial topic model designed to decode high-level spatial tissue architecture from multiplexed images.

Long-Term Survival and Biomarker Analysis Evaluating Neoadjuvant Plus Adjuvant Relatlimab (anti-LAG3) and Nivolumab (anti-PD1) in Patients With Resectable Melanoma.

Immune checkpoint blockade (ICB) has revolutionized outcomes for patients with melanoma across multiple disease settings. In patients with advanced, unresectable disease, the ICB combination of nivolumab (anti-PD1) and relatlimab (anti-LAG-3) has demonstrated improved clinical outcomes compared with nivolumab monotherapy. There exists an unmet need to identify biomarkers that predict response to this combination regimen and rational therapeutic strategies to overcome resistance.

Programmed death ligand-1 PET imaging in patients with melanoma: a pilot study.

Programmed death ligand-1 (PD-L1) is an inducible protein heterogeneously expressed in melanoma. Assessment of PD-L1 expression is challenging and standard immunohistochemistry (IHC) requires biopsies and cannot capture heterogeneity of expression. Noninvasive imaging methods provide evaluation of expression across lesions in the body.

Natural Language Processing of Radiology Reports to Assess Survival in Patients with Advanced Melanoma.

: To use natural language processing (NLP) to extract large-scale data from the CT radiology reports of patients with advanced melanoma treated with immunotherapy and to determine whether liver metastases affect survival. : Patient criteria (M1 disease subclassified into M1a, M1b, or M1c) as well as alternative criteria (M1 with advanced melanoma, imaged with CT chest, abdomen, and pelvis from July 2014-March 2019) were included retrospectively. NLP was used to identify metastases from CT reports, and then patients were classified according to American Joint Committee on Cancer (AJCC) staging disease subclassified into M1L+ or M1L-, indicating whether liver metastases were present or not).

Sarcoid-like reactions in patients treated with checkpoint inhibitors for advanced solid tumors.

Importance: While new intrathoracic adenopathy in a patient with cancer can represent progression of disease, the differential diagnosis is broad. Sarcoid-like reactions (SLR) remain an underreported source of lymphadenopathy in patients treated with immune checkpoint inhibitors (ICI), with limited reports in patients with cancers other than melanoma.

Objective: To characterize SLRs among patients treated with ICI for advanced solid tumors.

Management and Outcomes of Clostridioides difficile Infection in Patients on Immune Checkpoint Inhibitors.

Background: Data on the severity, management, and outcomes of Clostridioides difficile infection (CDI) in patients presenting with diarrhea while receiving immune checkpoint inhibitors (ICIs) are limited. This study aimed to evaluate the course of CDI in this population and the overlapping diagnosis of immune-related enterocolitis (irEC).

Methods: This retrospective cohort included ICI-treated patients who presented with diarrhea and underwent CDI stool nucleic acid amplification PCR testing at Memorial Sloan Kettering Cancer Center between July 2015 and July 2021.

Top advances of the year: Neoadjuvant immunotherapy in melanoma.

Overall, much progress was made in 2024 in the realm of neoadjuvant immunotherapy including the firm establishment of neoadjuvant immunotherapy as superior to only adjuvant immunotherapy for patients with resectable stage III melanoma with the NADINA trial results. However, unanswered questions remain regarding the optimal neoadjuvant immunotherapy regimen, long-term outcomes after modifying adjuvant approaches based on pathologic response, and if additional measurements of anti-tumor efficacy, in addition to pathologic response, can further help tailor adjuvant therapy decisions.

Quantitatively defined stromal B cell aggregates are associated with response to checkpoint inhibitors in unresectable melanoma.

Multiplex immunofluorescence (mIF) is a promising tool for immunotherapy biomarker discovery in melanoma and other solid tumors. mIF captures detailed phenotypic information of immune cells in the tumor microenvironment, as well as spatial data that can reveal biologically relevant interactions among cell types. Given the complexity of mIF data, the development of automated analysis pipelines is crucial for advancing biomarker discovery.

Error-corrected flow-based sequencing at whole-genome scale and its application to circulating cell-free DNA profiling.

Differentiating sequencing errors from true variants is a central genomics challenge, calling for error suppression strategies that balance costs and sensitivity. For example, circulating cell-free DNA (ccfDNA) sequencing for cancer monitoring is limited by sparsity of circulating tumor DNA, abundance of genomic material in samples and preanalytical error rates. Whole-genome sequencing (WGS) can overcome the low abundance of ccfDNA by integrating signals across the mutation landscape, but higher costs limit its wide adoption.

Longitudinal Genomic Analysis to Fine-tune Targeted Therapy: Results of the Phase II LOGIC 2 Trial in Patients with BRAFV600-Mutant Metastatic Melanoma.

Purpose: LOGIC 2 (NCT02159066), a multicenter, open-label, two-part, phase II study, assessed encorafenib plus binimetinib combined with a third targeted agent after tumor progression on encorafenib plus binimetinib in patients with locally advanced, unresectable or metastatic BRAFV600-mutant melanoma.

Patients And Methods: Adults with locally advanced, unresectable or metastatic BRAFV600-mutant melanoma who were BRAF inhibitor/MEK inhibitor (BRAFi/MEKi) treatment-naïve or pretreated received encorafenib plus binimetinib (part I/run-in). Based on the genomic testing at disease progression following encorafenib plus binimetinib, patients were assigned to one of four treatment arms to receive encorafenib plus binimetinib with an appropriate molecularly targeted agent (ribociclib, infigratinib, capmatinib, or buparlisib; part II).

Artificial Intelligence for Drug Discovery: An Update and Future Prospects.

Artificial intelligence (AI) has become a pivotal tool for medical image analysis, significantly enhancing drug discovery through improved diagnostics, staging, prognostication, and response assessment. At a high level, AI-driven image analysis enables the quantification and synthesis of previously qualitative imaging characteristics, facilitating the identification of novel disease-specific biomarkers, patient risk stratification, prognostication, and adverse event prediction. In addition, AI can assist in response assessment by capturing changes in imaging "phenotype" over time, allowing for optimized treatment plans based on real-time analysis.

Randomized clinical trial of a digital integrative medicine intervention among patients undergoing active cancer treatment.

Exercise and mindfulness-based interventions have growing evidence for managing fatigue and comorbid symptoms; however, packaging them in a cohesive digital way for patients undergoing cancer treatment has not been evaluated. We conducted a randomized controlled trial to assess the impact of a 12 week digital integrative medicine program, Integrative Medicine at Home (IM@Home), versus enhanced usual care on fatigue severity (primary outcome), comorbid symptoms and acute healthcare utilization (secondary outcomes), in 200 patients with solid tumors experiencing fatigue during treatment. Fatigue severity decreased more in IM@Home than in the control (1.

Intratumoral vidutolimod in combination with PD-1 blockade in locoregionally advanced melanoma.

Combinatorial immunotherapy may improve the efficacy of neoadjuvant checkpoint inhibitors in locoregionally advanced melanoma. In this issue of Cancer Cell, Davar and colleagues report a promising phase 2 neoadjuvant trial of the TLR9 agonist vidutolimod in combination with nivolumab. Analyses suggest a unique myeloid expression signature is associated with response.

Final, 10-Year Outcomes with Nivolumab plus Ipilimumab in Advanced Melanoma.

Background: Previous results from this trial showed longer overall survival after treatment with nivolumab plus ipilimumab or with nivolumab monotherapy than with ipilimumab monotherapy in patients with advanced melanoma. Given that patients with advanced melanoma are living longer than 7.5 years, longer-term data were needed to address new clinically relevant questions.

Spatial Immunophenotyping from Whole-Slide Multiplexed Tissue Imaging Using Convolutional Neural Networks.

The multiplexed immunofluorescence (mIF) platform enables biomarker discovery through the simultaneous detection of multiple markers on a single tissue slide, offering detailed insights into intratumor heterogeneity and the tumor-immune microenvironment at spatially resolved single cell resolution. However, current mIF image analyses are labor-intensive, requiring specialized pathology expertise which limits their scalability and clinical application. To address this challenge, we developed CellGate, a deep-learning (DL) computational pipeline that provides streamlined, end-to-end whole-slide mIF image analysis including nuclei detection, cell segmentation, cell classification, and combined immuno-phenotyping across stacked images.

Durable complete response in a patient with leptomeningeal melanoma after treatment with dabrafenib, trametinib, and nivolumab.

Leptomeningeal disease (LMD) is a devastating complication of melanoma with a dismal prognosis. We present the case of a young man with stage IV BRAF V600E mutant melanoma with lung, lymph node, and brain metastases initially treated with ipilimumab and nivolumab, who subsequently developed LMD. Upon change to BRAF/MEK targeted therapy with nivolumab, a durable complete response was achieved and remains ongoing, off treatment, 7 years from diagnosis.

Intratumoral Fc-optimized agonistic CD40 antibody induces tumor rejection and systemic antitumor immunity in patients with metastatic cancer.

While CD40 agonism is an attractive approach for activating antigen-presenting cells and initiating antitumor responses, previous attempts have encountered limited clinical efficacy coupled with toxicity. We previously demonstrated that interactions between the antibody Fc domain and the inhibitory receptor FcγRIIB are critical for enhanced antitumor activity. Here, we present the results of a phase 1 study on intratumoral administration of an anti-CD40 agonistic antibody (2141-V11) Fc-engineered to enhance FcγRIIB binding.

Ultrasensitive plasma-based monitoring of tumor burden using machine-learning-guided signal enrichment.

In solid tumor oncology, circulating tumor DNA (ctDNA) is poised to transform care through accurate assessment of minimal residual disease (MRD) and therapeutic response monitoring. To overcome the sparsity of ctDNA fragments in low tumor fraction (TF) settings and increase MRD sensitivity, we previously leveraged genome-wide mutational integration through plasma whole-genome sequencing (WGS). Here we now introduce MRD-EDGE, a machine-learning-guided WGS ctDNA single-nucleotide variant (SNV) and copy-number variant (CNV) detection platform designed to increase signal enrichment.

Breaking the Mold: Trailblazing Melanoma Therapy Beyond Checkpoint Through Innovative Approaches.

Melanoma has long been a difficult malignancy to treat with low response rates to standard chemotherapies. In recent years, the use of immune checkpoint inhibitors have demonstrated promising results, paving the way for the use of the rapidly developing novel immune targeting therapies. In this review, we look beyond immune checkpoint inhibitor treatments and summarize several emerging treatment strategies for melanoma, including neoantigen vaccines, conventional antibody drug-conjugates, and bispecific T-cell engager therapies.

Early On-Treatment Assessment of T Cells, Cytokines, and Tumor DNA with Adaptively Dosed Nivolumab + Ipilimumab: Final Results from the Phase 2 ADAPT-IT Study.

Purpose: The Adaptively Dosed ImmunoTherapy Trial (ADAPT-IT;NCT03122522) investigated adaptive ipilimumab discontinuation in melanoma based on early radiographic assessment. Initial findings indicated similar effectiveness compared with conventional nivolumab-ipilimumab (nivo-ipi). Exploratory biomarker analyses and final clinical results are now reported.