A cost-effectiveness analysis of sotorasib as second-line treatment for patients with KRAS-G12C-mutated metastatic non-small cell lung cancer (mNSCLC) in Switzerland.

Background And Objective: Because of the lack of effective targeted treatment options, docetaxel has long been the standard second-line therapy for patients with advanced non-small cell lung cancer, including the Kirsten rat sarcoma virus (KRAS) G12C mutation. The CodeBreak 200 trial demonstrated that sotorasib, a new drug targeting the G12C-mutated KRAS protein, modestly improved progression-free survival compared with docetaxel in patients whose cancer had progressed after receiving platinum chemotherapy and programmed cell death protein 1 (PD-1) / programmed death ligand 1 (PD-L1) inhibitors as first-line treatment. Consequently, sotorasib received temporary approval in Switzerland.

Outcomes following long-term disease control with immune checkpoint inhibitors in patients with advanced melanoma.

Immune checkpoint inhibitors (ICI) can achieve durable responses in patients with advanced melanoma, and results from clinical trials suggest cure may be possible for a subset of patients. Despite clinical trial data, little is known about the risk, character, and clinical outcome of late recurrences after ICI. This study aimed to explore the disease outcomes and survival in a cohort of patients with long-term responses to ICI.

A single-chain variable fragment-based bispecific T-cell activating antibody against CD117 enables T-cell mediated lysis of acute myeloid leukemia and hematopoietic stem and progenitor cells.

Acute myeloid leukemia (AML) derives from hematopoietic stem and progenitor cells (HSPCs). To date, no AML-exclusive, non-HSPC-expressed cell-surface target molecules for AML selective immunotherapy have been identified. Therefore, to still apply surface-directed immunotherapy in this disease setting, time-limited combined immune-targeting of AML cells and healthy HSPCs, followed by hematopoietic stem cell transplantation (HSCT), might be a viable therapeutic approach.

Inferior Overall Survival After Haploidentical Donor Lymphocyte Infusions in Relapsed Myeloid Neoplasms.

Objectives: Allogeneic hematopoietic stem cell transplantation (HSCT) effectively treats high-risk myeloid neoplasms, but relapses post-HSCT, particularly in acute myeloid leukemia (AML) and myelodysplastic neoplasms (MDS), pose significant challenges. Donor lymphocyte infusion (DLI) has been utilized, but its effectiveness, especially in haploidentical settings, remains insufficiently clarified, and graft-versus-host disease (GvHD) poses a substantial risk.

Methods: In this retrospective cohort study, 57 patients with AML or MDS who received DLI after allogeneic HSCT at our center from 2002 to 2023 were analyzed.

Patient recruitment into clinical studies of solid malignancies during the COVID-19 pandemic in a tertiary cancer center.

Background And Purpose: To analyze clinical trial activities and patient recruitment numbers into prospective clinical studies for solid malignancies during the COVID-19 pandemic in a tertiary cancer center.

Materials And Methods: Patient recruitment numbers in prospective clinical studies of solid malignancies were retrospectively analyzed for the years 2019 - 2021 at the Comprehensive Cancer Center Zurich (CCCZ). Changes in recruitment numbers were tested for association with organ-specific subunits, as well as organizational and treatment-related trial characteristics.

Fibrolytic vaccination against ADAM12 reduces desmoplasia in preclinical pancreatic adenocarcinomas.

A hallmark feature of pancreatic ductal adenocarcinoma (PDAC) is massive intratumoral fibrosis, designated as desmoplasia. Desmoplasia is characterized by the expansion of cancer-associated fibroblasts (CAFs) and a massive increase in extracellular matrix (ECM). During fibrogenesis, distinct genes become reactivated specifically in fibroblasts, e.

Molecular and functional landscape of malignant serous effusions for precision oncology.

Personalized treatment for patients with advanced solid tumors critically depends on the deep characterization of tumor cells from patient biopsies. Here, we comprehensively characterize a pan-cancer cohort of 150 malignant serous effusion (MSE) samples at the cellular, molecular, and functional level. We find that MSE-derived cancer cells retain the genomic and transcriptomic profiles of their corresponding primary tumors, validating their use as a patient-relevant model system for solid tumor biology.

High-throughput identification of repurposable neuroactive drugs with potent anti-glioblastoma activity.

Glioblastoma, the most aggressive primary brain cancer, has a dismal prognosis, yet systemic treatment is limited to DNA-alkylating chemotherapies. New therapeutic strategies may emerge from exploring neurodevelopmental and neurophysiological vulnerabilities of glioblastoma. To this end, we systematically screened repurposable neuroactive drugs in glioblastoma patient surgery material using a clinically concordant and single-cell resolved platform.

induces the expression of Lgr5 and stem cell properties in gastric target cells.

infection predisposes carriers to a high risk of developing gastric cancer. The cell-of-origin of antral gastric cancer is the Lgr5 stem cell. Here, we show that infection of antrum-derived gastric organoid cells with increases the expression of the stem cell marker Lgr5 as determined by immunofluorescence microscopy, qRT-PCR, and Western blotting, both when cells are grown and infected as monolayers and when cells are exposed to in 3D structures.

Cellular architecture shapes the naïve T cell response.

After antigen stimulation, naïve T cells display reproducible population-level responses, which arise from individual T cells pursuing specific differentiation trajectories. However, cell-intrinsic predeterminants controlling these single-cell decisions remain enigmatic. We found that the subcellular architectures of naïve CD8 T cells, defined by the presence (T) or absence (T) of nuclear envelope invaginations, changed with maturation, activation, and differentiation.

IL-1 in aging and pathologies of hematopoietic stem cells.

Defense-oriented inflammatory reactivity supports survival at younger age but might contribute to health impairments in modern, aging societies. The interleukin-1 (IL-1) cytokines are highly conserved and regulated, pleiotropic mediators of inflammation, essential to respond adequately to infection and tissue damage but also with potential host damaging effects when left unresolved. In this review, we discuss how continuous low-level IL-1 signaling contributes to aging-associated hematopoietic stem and progenitor cell (HSPC) functional impairments and how this inflammatory selective pressure acts as a driver of more profound hematological alterations, such as clonal hematopoiesis of indeterminate potential, and to overt HSPC diseases, like myeloproliferative and myelodysplastic neoplasia as well as acute myeloid leukemia.

Modulation of the neuronal response in human primary visual cortex by re-entrant projections during retinal input processing as manifest in the visual evoked potential.

Initial deflections in the visual evoked potential (VEP) reflect the neuronal process of extracting features from the retinal input; a process not modulated by re-entrant projections. Later deflections in the VEP reflect the neuronal process of combining features into an object, a process referred to as 'object closure' and modulated by re-entrant projections. Our earlier work indicated that the VEP reflects independent neuronal responses processing temporal - and spatial luminance contrast and that these responses arise from an interaction between forward and re-entrant input.

Omission of Axillary Dissection Following Nodal Downstaging With Neoadjuvant Chemotherapy.

Importance: Data on oncological outcomes after omission of axillary lymph node dissection (ALND) in patients with breast cancer that downstages from node positive to negative with neoadjuvant chemotherapy are sparse. Additionally, the best axillary surgical staging technique in this scenario is unknown.

Objective: To investigate oncological outcomes after sentinel lymph node biopsy (SLNB) with dual-tracer mapping or targeted axillary dissection (TAD), which combines SLNB with localization and retrieval of the clipped lymph node.

Optimizing the Design and Geometry of T Cell-Engaging Bispecific Antibodies Targeting CEA in Colorectal Cancer.

Metastatic colorectal cancer remains a leading cause of cancer-related deaths, with a 5-year survival rate of only 15%. T cell-engaging bispecific antibodies (TCBs) represent a class of biopharmaceuticals that redirect cytotoxic T cells toward tumor cells, thereby turning immunologically "cold" tumors into "hot" ones. The carcinoembryonic antigen (CEA) is an attractive tumor-associated antigen that is overexpressed in more than 98% of patients with colorectal cancer.

Preclinical evaluation of the efficacy of an antibody to human SIRPα for cancer immunotherapy in humanized mouse models.

Tumor-associated macrophages (TAMs) are abundant in the tumor microenvironment and are considered potential targets for cancer immunotherapy. To examine the antitumor effects of agents targeting human TAMs , we here established preclinical tumor xenograft models based on immunodeficient mice that express multiple human cytokines and have been reconstituted with a human immune system by transplantation of human CD34 hematopoietic stem and progenitor cells (HIS-MITRG mice). HIS-MITRG mice supported the growth of both human cell line (Raji)- and patient-derived B cell lymphoma as well as the infiltration of human macrophages into their tumors.

Patterns of progression on first line osimertinib in patients with EGFR mutation-positive advanced non-small cell lung cancer (NSCLC): A Swiss cohort study.

Aim: Osimertinib is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) approved for patients with EGFR mutated non-small cell lung cancer as first-line treatment. However, treatment resistance inevitably emerges and may present as oligo-progressive disease (OPD) or systemic progressive disease (SPD). The incidence of OPD on first-line osimertinib is unknown.

Inactivation of the tumor suppressor gene synergizes with to induce DNA damage in murine gastric stem and progenitor cells.

infection is a major risk factor for the development of gastric cancer. The bacteria reside in close proximity to gastric surface mucous as well as stem and progenitor cells. Here, we take advantage of wild-type and genetically engineered murine gastric organoids and organoid-derived monolayers to study the cellular targets of -induced DNA damage and replication stress and to explore possible interactions with preexisting gastric cancer driver mutations.

Twisted: Escape of epitope-edited healthy cells from immune attack.

Hematopoietic stem and progenitor cell-derived neoplasia is challenging to target by cell surface-directed immunotherapy due to lack of tumor cell-specific antigen identification. Marone et al. (2023.

Genome Editing in Engineered T Cells for Cancer Immunotherapy.

Advanced gene transfer technologies and profound immunological insights have enabled substantial increases in the efficacy of anticancer adoptive cellular therapy (ACT). In recent years, the U.S.

Acquired resistance to anti-PD1 therapy in patients with NSCLC associates with immunosuppressive T cell phenotype.

Immune checkpoint inhibitor treatment has the potential to prolong survival in non-small cell lung cancer (NSCLC), however, some of the patients develop resistance following initial response. Here, we analyze the immune phenotype of matching tumor samples from a cohort of NSCLC patients showing good initial response to immune checkpoint inhibitors, followed by acquired resistance at later time points. By using imaging mass cytometry and whole exome and RNA sequencing, we detect two patterns of resistance¨: One group of patients is characterized by reduced numbers of tumor-infiltrating CD8 T cells and reduced expression of PD-L1 after development of resistance, whereas the other group shows high CD8 T cell infiltration and high expression of PD-L1 in addition to markedly elevated expression of other immune-inhibitory molecules.