Phase II Dose-Randomized Study of Sunvozertinib in Platinum-Pretreated Non-Small Cell Lung Cancer With Epidermal Growth Factor Receptor Exon 20 Insertion Mutations (WU-KONG1B).

Purpose: WU-KONG1B (ClinicalTrials.gov identifier: NCT03974022) is a multinational phase II, dose-randomized study to assess the antitumor efficacy of sunvozertinib in pretreated patients with advanced non-small cell lung cancer (NSCLC) with epidermal growth factor receptor () exon 20 insertion mutations (exon20ins).

Methods: Eligible patients with advanced-stage exon20ins NSCLC were randomly assigned by 1:1 ratio to receive sunvozertinib 200 mg or 300 mg once daily (200 and 300 mg-rand cohorts).

Genetically determined body mass index is associated with diffuse large B-cell lymphoma in polygenic and Mendelian randomization analyses.

Obesity has been associated with non-Hodgkin lymphoma (NHL), but the evidence is inconclusive. We examined the association between genetically determined adiposity and four common NHL subtypes: diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, chronic lymphocytic leukemia, and marginal zone lymphoma, using eight genome-wide association studies of European ancestry (N = 10,629 cases, 9505 controls) and constructing polygenic scores for body mass index (BMI), waist-to-hip ratio (WHR), and waist-to-hip ratio adjusted for BMI (WHRadjBMI). Higher genetically determined BMI was associated with an increased risk of DLBCL [odds ratio (OR) per standard deviation (SD) = 1.

Efficacy of Stereotactic Ablative Body Radiotherapy (SABR) in uncommon subtypes of primary kidney cancer: An analysis from the International Radiosurgery Oncology Consortium of the Kidney.

Background: While stereotactic ablative body radiotherapy (SABR) is associated with excellent local control for primary renal cell carcinoma (RCC), outcomes based on clear-cell (ccRCC) and non-clear cell (nccRCC) histologies are not well defined.

Methods And Materials: Individual data of adult patient with biopsy confirmed primary RCC receiving SABR between 2007 and 2021 from 16 institutions in Australia, Canda, Germany, Japan and USA pooled. Patients with metastatic disease or upper tract urothelial carcinoma were excluded.

The effect of TERT promoter mutation on predicting meningioma outcomes: a multi-institutional cohort analysis.

Background: Molecular aberrations have been incorporated into tumour classification guidelines of meningioma. TERT-promoter (TERTp) mutation is associated with worse prognosis and is designated a WHO grade 3 biomarker. However, it remains unclear whether TERTp mutation is context-dependent, with other co-occurring genetic alterations potentially driving its association with prognosis.

Prospective assessment of prognostic significance of malignant peritoneal cytology in endometrial cancer: An NRG Oncology / Gynecologic Oncology Group study on GOG-210 protocol.

Objective: To examine the association between malignant peritoneal cytology and survival outcomes in endometrial cancer.

Methods: This was an ancillary analysis of prospectively collected surgical-pathological data in the NRG Oncology / Gynecologic Oncology Group study on GOG-210 protocol. The study population included 2383 patients with stage I-III endometrial cancer from 2003 to 2011.

CXCR6 promotes dermal CD8+ T cell survival and transition to long-term tissue residence.

Tissue resident memory T cells (TRM) provide protection against local re-infection, and yet the interstitial signals that govern their formation and persistence remain poorly defined. Here, we show that antigen-dependent induction of the chemokine receptor CXCR6, is a conserved adaptation to peripheral tissue infiltration that promotes TRM formation after viral infection. Deficient TRM formation in the absence of CXCR6 was not explained by trafficking as CXCR6 was not required for tissue entry, was dispensable for the early accumulation of antigen-specific CD8+ T cells in skin, and did not restrain their exit.

Nerve-associated macrophages control adipose homeostasis across lifespan and restrain age-related inflammation.

Age-related inflammation or 'inflammaging' increases disease burden and controls lifespan. Adipose tissue macrophages (ATMs) are critical regulators of inflammaging; however, the mechanisms involved are not well understood in part because the molecular identities of niche-specific ATMs are unknown. Using intravascular labeling to exclude circulating myeloid cells followed by single-cell sequencing with orthogonal validation via multiparametric flow cytometry, we define sex-specific changes and diverse populations of resident ATMs through lifespan in mice.

Metabolomic signatures of hypocaloric dietary interventions associate with breast cancer risk in the Nurses' Health Study II.

Background: An individual's metabolic state plays a critical role in breast cancer (BC) risk, influenced by factors such as obesity and insulin signaling. Hypocaloric diets induce metabolic changes that influence these metabolic factors, thereby potentially influencing BC risk. However, it remains unclear whether metabolic profiles like those induced by such beneficial diets are associated with BC risk.

Current and Emerging Fluorescence-Guided Techniques in Glioma to Enhance Resection.

Maximal safe surgical resection remains a critical component of glioblastoma (GBM) management, improving both survival and quality of life. However, complete tumor removal is hindered by the infiltrative nature of GBM and its proximity to eloquent brain regions. Fluorescence-guided surgery (FGS) has emerged as a valuable tool to enhance intraoperative tumor visualization and optimize resection outcomes.

Case Report: Unlocking opportunities in HER2-targeted antibody-drug conjugates for bulky leptomeningeal metastatic breast cancer.

Leptomeningeal carcinomatosis (LC) is a severe complication of metastatic breast cancer (mBC), with rising incidence. The prognosis for patients with LC has been poor, with a median overall survival of approximately four months. However, recent therapeutic advances, in particular the introduction of trastuzumab deruxtecan have dramatically changed the landscape of CNS metastases and improved outcomes.

Clinical strategies for lung cancer management: Recommendations from the Bridging the Gaps Lung Cancer Consensus Conference 2024.

Clinical practice guidelines for nonsmall cell lung cancer (NSCLC) and small cell lung cancer include recommendations based on high-level clinical trial evidence, but complex clinical questions are frequently seen in real-world practice that are not clearly answered by prospective trial data. To address these questions, the Bridging the Gaps Lung Cancer Consensus Conference 2024 (BtG LCCC 2024) convened to develop US-focused expert guidance for clinical situations in which level 1 evidence is lacking. At BtG LCCC 2024, a multidisciplinary expert panel discussed ongoing clinical issues in small cell lung cancer management, targeted therapy in EGFR-mutated NSCLC, management of early stage NSCLC, identification and management of non-EGFR oncogene-driven NSCLC, and use of immunotherapy in advanced/metastatic NSCLC.

Development of Mouse-Derived Organoid Lines from Fallopian Tube Epithelial Cells for High Grade Serous Ovarian Carcinoma Modeling.

Effective modeling of diseases in realistic environments is crucial to improve our understanding of diverse pathologies. In this aspect, organoids offer a more faithful environment than their classical two-dimensional counterparts in vitro. Similarly, syngeneic murine models also allow researchers to investigate more complete tumor-host interactions, such as with the immune system, in vivo.

Deep mutational scanning reveals EGFR mutations conferring resistance to the 4th-generation EGFR tyrosine kinase inhibitor BLU-945.

Fourth-generation EGFR tyrosine kinase are in development to overcome common resistance mutations. We performed deep mutational scanning (DMS) of the EGFR kinase domain in the context of L858R by introducing a saturation library of ~17,000 variants into Ba/F3 cells. DMS library-expressing cells were exposed to osimertinib or BLU-945 to identify escape mutations.

Temporal genomic dynamics shape clinical trajectory in multiple myeloma.

Multiple myeloma evolution is characterized by the accumulation of genomic drivers over time. To unravel this timeline and its impact on clinical outcomes, we analyzed 421 whole-genome sequences from 382 patients. Using clock-like mutational signatures, we estimated a time lag of two to four decades between the initiation of events and diagnosis.

Targeting FSP1 triggers ferroptosis in lung cancer.

Pre-clinical and clinical studies have demonstrated how dietary antioxidants or mutations activating antioxidant metabolism promote cancer, highlighting a central role oxidative stress in tumorigenesis. However, it is unclear if oxidative stress ultimately increases to a point of cell death. Emerging evidence indicates that cancer cells are susceptible to ferroptosis, a form of cell death triggered by uncontrolled lipid peroxidation.

Paired plus-minus sequencing is an ultra-high throughput and accurate method for dual strand sequencing of DNA molecules.

Distinguishing real biological variation in the form of single-nucleotide variants (SNVs) from errors is a major challenge for genome sequencing technologies. This is particularly true in settings where SNVs are at low frequency such as cancer detection through liquid biopsy, or human somatic mosaicism. State-of-the-art molecular denoising approaches for DNA sequencing rely on duplex sequencing, where both strands of a single DNA molecule are sequenced to discern true variants from errors arising from single stranded DNA damage.

Automating the Referral of Bone Metastases Patients With and Without the Use of Large Language Models.

Background And Objectives: Bone metastases, affecting more than 4.8% of patients with cancer annually, and particularly spinal metastases require urgent intervention to prevent neurological complications. However, the current process of manually reviewing radiological reports leads to potential delays in specialist referrals.

Belzutifan-Associated Hypoxia: A Review of the Novel Therapeutic, Proposed Mechanisms of Hypoxia, and Management Recommendations.

Belzutifan is a hypoxia-inducible factor-2α (HIF-2α) inhibitor that received FDA approval in 2021 for treating cancers resulting from von Hippel-Lindau (VHL) disease, including clear cell renal cell carcinoma (ccRCC), followed by approval in 2023 for sporadic ccRCC that has progressed through multiple lines of therapy. HIF-2α is a promising drug target, as VHL is commonly inactivated in ccRCC, which results in HIF-2α-mediated signaling that is considered central to tumorigenesis. Belzutifan has demonstrated efficacy in clinical trials in the first-line and subsequent line settings, and in combination with tyrosine kinase inhibitors.

A Hotspot Phosphorylation Site on SHP2 Drives Oncoprotein Activation and Drug Resistance.

SHP2 is a phosphatase and a critical mediator of receptor tyrosine kinase (RTK)-driven RAS/mitogen-activated protein kinase (MAPK) signaling. Despite promising preclinical data, SHP2 inhibitors have shown minimal clinical efficacy, with no defined clinical mechanisms of primary resistance. Here, we elucidate phosphorylation of SHP2 at tyrosine 62 (pY62) as a hotspot phosphorylation site in the proteome and RTK-driven tumor types in patients.

Helminth infections affect host immune responses to viral infections and vaccines.

Helminths are highly prevalent in many regions of the world. Due to the chronic nature of most helminth infections, these parasites are proficient immunomodulators of their hosts. This modulation often leads to skewed or even impaired immune responses against unrelated antigens, such as viruses and vaccines, which can be both beneficial and detrimental for the host.

Improved Mutation Detection in Duplex Sequencing Data with Sample-Specific Error Profiles.

Duplex sequencing enables highly accurate detection of rare somatic mutations, but existing variant callers often rely on protocol-specific heuristics that limit sensitivity, reproducibility, and cross-study comparability. We present DupCaller, a probabilistic variant caller that builds sample-specific error profiles and applies a strand-aware statistical model for mutation detection. Across 50 synthetic datasets, DupCaller identified 1.

ApaH decaps NpN-capped RNAs in two alternative orientations.

Enigmatic dinucleoside tetraphosphates, known as 'alarmones' (NpNs), have recently been shown to function in bacteria as precursors to Np caps on transcripts, likely influencing RNA longevity and cellular adaptation to stress. In proteobacteria, ApaH is the predominant enzyme that hydrolyzes NpNs and decaps Np-capped RNAs to initiate their 5'-end-dependent degradation. Here we conducted a biochemical and structural study to uncover the catalytic mechanism of Escherichia coli ApaH, a prototypic symmetric NpN hydrolase, on various NpNs and Np-capped RNAs.

Dual Immune Check Point Blockade in -Unmethylated Newly Diagnosed Glioblastoma: NRG Oncology BN007, a Randomized Phase II/III Clinical Trial.

Purpose: New therapies for glioblastoma are needed, especially -unmethylated (u) disease. NRG Oncology BN002 (phase I) demonstrated safety and suggested efficacy of ipilimumab (ipi) with nivolumab (nivo) in newly diagnosed glioblastoma, leading to this phase II/III trial.

Methods: Adults with newly diagnosed u glioblastoma and Karnofsky performance status (KPS) ≥70 were randomly assigned to radiotherapy with either immunotherapy (ipi and nivo) or temozolomide (TMZ), stratified by recursive partitioning analysis (RPA) class and intention to use tumor treating fields.

NKTR-255 Enhances Complete Response Following CD19 CAR-T in Patients with Relapsed/Refractory Large B-cell Lymphoma.

Autologous T-cells engineered to express CD19-directed chimeric antigen receptor (CAR) have shown high overall response rates in treatment-refractory large B-cell lymphoma (LBCL). However, more than half of patients do not attain a durable response and will eventually relapse. Thus, strategies to improve long-term efficacy of CAR T-cell products are needed.