Real-World outcomes of Non-Small cell lung cancer patients harbouring KRAS G12C and KRAS G12D mutations.

Background: KRAS G12D and G12C mutations have distinct biological traits influencing treatment response. This study examines real-world demographics, clinical characteristics, and first-line treatment outcomes in metastatic non-small-cell lung cancer (NSCLC) patients with these mutations.

Methods: This retrospective, multi-institution observational study used data from the AURORA database.

Spatial interaction mapping of PD-1/PD-L1 in head and neck cancer reveals the role of macrophage-tumour barriers associated with immunotherapy response.

Background: Mucosal head and neck squamous cell carcinoma (HNSCC) is often diagnosed at an advanced stage, where the prognosis is poor due to the high rates of recurrence and metastasis. With approximately one million new cases projected in 2024, worldwide mortality of HNSCC is estimated to reach 50% of detected cases the same year. Patients with early-stage tumours showed a 50-60% five-year survival rate in the US.

Durvalumab, Tremelimumab, and Platinum Chemotherapy in Mutation-Positive NSCLC: An Open-Label Phase 2 Trial (ILLUMINATE).

Introduction: -mutant NSCLC is associated with low mutation burden and low levels of PD-L1 expression. We conducted a phase 2 trial to determine the efficacy of durvalumab, tremelimumab, and platinum-pemetrexed in mutant NSCLC after progression with EGFR tyrosine kinase inhibitors (TKIs).

Methods: Participants were treated with induction durvalumab, tremelimumab, and platinum-pemetrexed, followed by durvalumab-pemetrexed maintenance.

A signal-seeking phase 2 study of Trastuzumab emtansine in tumours harbouring HER2 amplification or mutation.

This single-arm phase II non-randomised trial (ACTRN12619001265167) evaluated trastuzumab emtansine in solid cancers with HER2 amplification or mutation detected by comprehensive genomic profiling. The primary objective was objective response (OR), while secondary objectives included the time to progression (TTP) on study to TTP on prior therapy ratio, progression-free survival (PFS) and overall survival (OS). The cohort included 16 tumours with HER2 mutations (group 1) and 16 with HER2 amplification (group 2).

Spatial dynamics of tertiary lymphoid aggregates in head and neck cancer: insights into immunotherapy response.

Background: Recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) generally has a poor prognosis for patients with limited treatment options. While incorporating immune checkpoint inhibitors (ICIs) has now become the standard of care, the efficacy is variable, with only a subset of patients responding. The complexity of the tumor microenvironment (TME) and the role of tertiary lymphoid structures (TLS) have emerged as critical determinants for immunotherapeutic response.

Spatial resolution of the head and neck cancer tumor microenvironment to identify tumor and stromal features associated with therapy response.

Head and neck cancer (HNC) is the seventh most common cancer globally, resulting in 440 000 deaths per year. While there have been advancements in chemoradiotherapy and surgery, relapse occurs in more than half of HNCs, and these patients have a median survival of 10 months and a 2-year survival of < 20%. Only a subset of patients displays durable benefits from immunotherapies in metastatic and recurrent HNC, making it critical to understand the tumor microenvironment (TME) underpinning therapy responses in HNC.

Spatial proteomic profiling of tumor and stromal compartments in non-small-cell lung cancer identifies signatures associated with overall survival.

Objectives: Non-small-cell lung carcinoma (NSCLC) is the most prevalent and lethal form of lung cancer. The need for biomarker-informed stratification of targeted therapies has underpinned the need to uncover the underlying properties of the tumor microenvironment (TME) through high-plex quantitative assays.

Methods: In this study, we profiled resected NSCLC tissues from 102 patients by targeted spatial proteomics of 78 proteins across tumor, immune activation, immune cell typing, immune-oncology, drug targets, cell death and PI3K/AKT modules to identify the tumor and stromal signatures associated with overall survival (OS).

Characterisation of circulating tumor-associated and immune cells in patients with advanced-stage non-small cell lung cancer.

Objectives: Globally, non-small cell lung cancer (NSCLC) is the most prevalent form of lung cancer and the leading cause of cancer-related deaths. Tumor-associated circulating cells in NSCLC can have a wide variety of morphological and phenotypic characteristics, including epithelial, immunological or hybrid subtypes. The distinctive characteristics and potential clinical significance of these cells in patients with NSCLC are explored in this study.

Sequence- and Structure-Dependent Cytotoxicity of Phosphorothioate and 2'--Methyl Modified Single-Stranded Oligonucleotides.

Single-stranded oligonucleotides (SSOs) are a rapidly expanding class of therapeutics that comprises antisense oligonucleotides, microRNAs, and aptamers, with ten clinically approved molecules. Chemical modifications such as the phosphorothioate backbone and the 2'--methyl ribose can improve the stability and pharmacokinetic properties of therapeutic SSOs, but they can also lead to toxicity and through nonspecific interactions with cellular proteins, gene expression changes, disturbed RNA processing, and changes in nuclear structures and protein distribution. In this study, we screened a mini library of 277 phosphorothioate and 2'--methyl-modified SSOs, with or without mRNA complementarity, for cytotoxic properties in two cancer cell lines.

Spatial insights into immunotherapy response in non-small cell lung cancer (NSCLC) by multiplexed tissue imaging.

The spatial localisation of immune cells within tumours are key to understand the intercellular communications that can dictate clinical outcomes. Here, we demonstrate an analysis pipeline for highly multiplexed CODEX data to phenotype and profile spatial features and interactions in NSCLC patients that subsequently received PD1 axis immunotherapy. We found that regulatory T cells (Tregs) are enriched in non-responding patients and this was consistent with their localization within stromal and peripheral tumour-margins.

Targeting the hSSB1-INTS3 Interface: A Computational Screening Driven Approach to Identify Potential Modulators.

Human single-stranded DNA binding protein 1 (hSSB1) forms a heterotrimeric complex, known as a sensor of single-stranded DNA binding protein 1 (SOSS1), in conjunction with integrator complex subunit 3 (INTS3) and C9ORF80. This sensory protein plays an important role in homologous recombination repair of double-strand breaks in DNA to efficiently recruit other repair proteins at the damaged sites. Previous studies have identified elevated hSSB1-mediated DNA repair activities in various cancers, highlighting its potential as an anticancer target.

In situ characterization of the tumor microenvironment.

The development of new therapies for cancer is underpinned by an increasing need to comprehensively characterize the tumor microenvironment (TME). While traditional approaches have relied on bulk or single-cell approaches, these are limited in their ability to provide cellular context. Deconvolution of the complex TME is fundamental to understanding tumor dynamics and treatment resistance.

Metabolomics at the tumor microenvironment interface: Decoding cellular conversations.

Cancer heterogeneity remains a significant challenge for effective cancer treatments. Altered energetics is one of the hallmarks of cancer and influences tumor growth and drug resistance. Studies have shown that heterogeneity exists within the metabolic profile of tumors, and personalized-combination therapy with relevant metabolic interventions could improve patient response.

Liquid Biopsy Snapshots of Key Phosphoproteomic Pathways in Lung Cancer Patients for Diagnosis and Therapy Monitoring.

Phosphorylation is a post-translational modification in proteins that changes protein conformation and activity for regulating signal transduction pathways. This mechanism is frequently impaired in lung cancer, resulting in permanently active constitutive phosphorylation to initiate tumor growth and/or reactivate pathways in response to therapy. We developed a multiplexed phosphoprotein analyzer chip (MPAC) that enables rapid (detection time: 5 min) and sensitive (LOD: 2 pg/μL) detection of protein phosphorylation and presents phosphoproteomic profiling of major phosphorylation pathways in lung cancer.

Compartmentalized spatial profiling of the tumor microenvironment in head and neck squamous cell carcinoma identifies immune checkpoint molecules and tumor necrosis factor receptor superfamily members as biomarkers of response to immunotherapy.

Mucosal head and neck squamous cell carcinoma (HNSCC) are the seventh most common cancer, with approximately 50% of patients living beyond 5 years. Immune checkpoint inhibitors (ICIs) have shown promising results in patients with recurrent or metastatic (R/M) disease, however, only a subset of patients benefit from immunotherapy. Studies have implicated the tumor microenvironment (TME) of HNSCC as a major factor in therapy response, highlighting the need to better understand the TME, particularly by spatially resolved means to determine cellular and molecular components.

Multi-omic and spatial dissection of immunotherapy response groups in non-small cell lung cancer.

The composition and activation status of the cellular milieu contained within the tumour microenvironment (TME) is becoming increasingly recognized as a driving factor for immunotherapy response. Here, we employed multiplex immunohistochemistry (mIHC), and digital spatial profiling (DSP) to capture the targeted immune proteome and transcriptome of tumour and TME compartments from an immune checkpoint inhibitor (ICI)-treated (n = 41) non-small cell lung cancer (NSCLC) patient cohort. We demonstrate by mIHC that the interaction of CD68 macrophages with PD1 , FoxP3 cells is enriched in ICI refractory tumours (p = 0.

transcription is an early predictor for COVID-19 outcomes, a multi-cohort observational study.

Purpose: Robust biomarkers that predict disease outcomes amongst COVID-19 patients are necessary for both patient triage and resource prioritisation. Numerous candidate biomarkers have been proposed for COVID-19. However, at present, there is no consensus on the best diagnostic approach to predict outcomes in infected patients.

Transcriptomic profiling of cardiac tissues from SARS-CoV-2 patients identifies DNA damage.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is known to present with pulmonary and extra-pulmonary organ complications. In comparison with the 2009 pandemic (pH1N1), SARS-CoV-2 infection is likely to lead to more severe disease, with multi-organ effects, including cardiovascular disease. SARS-CoV-2 has been associated with acute and long-term cardiovascular disease, but the molecular changes that govern this remain unknown.

Immunotherapeutic targets in non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) is one of the most common types of cancer in the world and has a 5-year survival rate of ~20%. Immunotherapies have shown promising results leading to durable responses, however, they are only effective for a subset of patients. To determine the best therapeutic approach, a thorough and in-depth profiling of the tumour microenvironment (TME) is required.

Understanding the tumor microenvironment in head and neck squamous cell carcinoma.

Head and neck squamous cell carcinoma (HNSCC) represents a heterogeneous group of tumors. While significant progress has been made using multimodal treatment, the 5-year survival remains at 50%. Developing effective therapies, such as immunotherapy, will likely lead to better treatment of primary and metastatic disease.

Dissecting Tissue Compartment-Specific Protein Signatures in Primary and Metastatic Oropharyngeal Squamous Cell Carcinomas.

Head and neck squamous cell carcinoma (HNSCC) often presents with locoregional or distant disease, despite multimodal therapeutic approaches, which include surgical resection, chemoradiotherapy, and more recently, immunotherapy for metastatic or recurrent HNSCC. Therapies often target the primary and nodal regional HNSCC sites, and their efficacy at controlling occult distant sites remains poor. While our understanding of the tumor microenvironment conducive to effective therapies is increasing, the biology underpinning locoregional sites remains unclear.

Immune Checkpoint Inhibitors in Cancer Therapy.

The discovery of immune checkpoint proteins such as PD-1/PDL-1 and CTLA-4 represents a significant breakthrough in the field of cancer immunotherapy. Therefore, humanized monoclonal antibodies, targeting these immune checkpoint proteins have been utilized successfully in patients with metastatic melanoma, renal cell carcinoma, head and neck cancers and non-small lung cancer. The US FDA has successfully approved three different categories of immune checkpoint inhibitors (ICIs) such as PD-1 inhibitors (Nivolumab, Pembrolizumab, and Cemiplimab), PDL-1 inhibitors (Atezolimumab, Durvalumab and Avelumab), and CTLA-4 inhibitor (Ipilimumab).

The Role of Circulating Biomarkers in Lung Cancer.

Lung cancer is the leading cause of cancer morbidity and mortality worldwide and early diagnosis is crucial for the management and treatment of this disease. Non-invasive means of determining tumour information is an appealing diagnostic approach for lung cancers as often accessing and removing tumour tissue can be a limiting factor. In recent years, liquid biopsies have been developed to explore potential circulating tumour biomarkers which are considered reliable surrogates for understanding tumour biology in a non-invasive manner.