Background: The identification of reliable prognostic biomarkers is crucial for optimizing cancer treatment strategies, especially in the era of personalized medicine. This systematic review and meta-analysis evaluate the prognostic significance of the neutrophil-to-eosinophil ratio (NER) in various cancer types, with a focus on its association with overall survival (OS) and progression-free survival (PFS). Methods: We conducted a systematic literature search across PubMed, Scopus, and Web of Science databases for studies published up to 28 July 2024. We performed the meta-analyses with the generic inverse variance method with a random effects model and reported hazard ratios (HR) with 95% confidence intervals (CI). Results: The comprehensive literature search identified 10 studies comprising 2351 patients. Pooled analyses demonstrated that elevated pretreatment NER levels were significantly correlated with poorer OS (HR: 1.74, 95% CI: 1.28–2.36, p < 0.001) and PFS (HR: 1.53, 95% CI: 1.21–1.95, p < 0.001). Subgroup analyses confirmed a consistent adverse association between high NER and OS across various tumor types and geographic locations, although results from studies conducted in the Far East did not reach statistical significance. Conclusions: This meta-analysis demonstrates that elevated NER is associated with poorer OS and PFS in cancer patients, suggesting its potential utility as a non-invasive prognostic marker. Further validation in large, prospective studies is warranted to establish NER’s role in guiding personalized treatment strategies across diverse oncologic contexts.

Sarcoidosis is an idiopathic inflammatory disorder that is commonly treated with glucocorticoids. An imprecise understanding of the immunologic changes underlying sarcoidosis has limited therapeutic progress. Here in this open-label trial (NCT03910543), 10 patients with cutaneous sarcoidosis are treated with tofacitinib, a Janus kinase inhibitor. The primary outcome is the change in the cutaneous sarcoidosis activity and morphology instrument (CSAMI) activity score after 6 months of treatment. Secondary outcomes included change in internal organ involvement, molecular parameters, and safety. All patients experience improvement in their skin with 6 patients showing a complete response. Improvement in internal organ involvement is also observed. CD4⁺ T cell-derived IFN-γ is identified as a central cytokine mediator of macrophage activation in sarcoidosis. Additional type 1 cytokines produced by distinct cell types, including IL-6, IL-12, IL-15 and GM-CSF, also associate with pathogenesis. Suppression of the activity of these cytokines, especially IFN-γ, correlates with clinical improvement. Our results thus show that tofacitinib treatment is associated with improved sarcoidosis symptoms, and predominantly acts by inhibiting type 1 immunity.

Despite recent advances, biliary tract cancer (BTC) is traditionally known as being hard to treat with a poor prognosis. Recent state-of-the-art genomic technologies such as next-generation sequencing (NGS) revolutionized cancer management and shed light on the genomic landscape of BTCs. There are ongoing clinical trials to assess the efficacy of HER2-blocking antibodies or drug conjugates in BTCs with HER2 amplifications. However, HER2 amplifications may not be the sole eligibility factor for these clinical trials. In this review, we aimed to comprehensively examine the role of somatic HER2 alterations and amplifications in patient stratification and provide an overview of the current state of ongoing clinical trials.

KRAS mutations are common driver oncogenes associated with the development of several solid tumors. KRAS oncogene has been considered a highly challenging target for drug development because of structural features, including the lack of deep groove on its catalytic unit. However, by leveraging cysteine residues, covalent KRAS inhibitors irreversibly trap KRAS G12C mutants in their inactive GDP-bound state. These agents have resulted in significant clinical responses among patients with KRAS G12C-mutant solid tumors, including patients with colorectal cancer (CRC). Other allele-specific inhibitors of KRAS oncogene and panKRAS and panRAS inhibitors are also currently being investigated in clinical trials. This review article overviews recent clinical progress on KRAS G12C targeting for the management of patients with KRAS G12C-mutant CRC and provides an update on other RAS targeting approaches. We also discuss the unique biological features of RAS-mutant CRC, which require the combination of KRAS inhibitors and anti-epidermal growth factor receptor therapy, and elaborate on resistance mechanisms and novel therapeutic avenues that may define future treatment paradigms of patients with RAS-mutant CRC.

Prostate cancers adapt to androgen receptor (AR) pathway inhibitors and progress to castration resistance due to ongoing AR expression and function. To counter this, we developed a new approach to modulate the AR and inhibit castration-resistant prostate cancer (CRPC) using multivalent peptoid conjugates (MPC) that contain multiple copies of the AR-targeting ligand ethisterone attached to a peptidomimetic scaffold. Here, we investigated the antitumor effects of compound MPC309, a trivalent display of ethisterone conjugated to a peptoid oligomer backbone that binds to the AR with nanomolar affinity. MPC309 exhibited potent antiproliferative effects on various enzalutamide-resistant prostate cancer models, including those with AR splice variants, ligand-binding mutations, and noncanonical AR gene expression programs, as well as mouse prostate organoids harboring defined genetic alterations that mimic lethal human prostate cancer subtypes. MPC309 is taken up by cells through macropinocytosis, an endocytic process more prevalent in cancer cells than in normal ones, thus providing an opportunity to target tumors selectively. MPC309 triggers a distinct AR transcriptome compared with DHT and enzalutamide, a clinically used antiandrogen. Specifically, MPC309 enhances the expression of differentiation genes while reducing the expression of genes needed for cell division and metabolism. Mechanistically, MPC309 increases AR chromatin occupancy and alters AR interactions with coregulatory proteins in a pattern distinct from DHT. In xenograft studies, MPC309 produced significantly greater tumor suppression than enzalutamide. Altogether, MPC309 represents a promising new AR modulator that can combat resistant disease by promoting an AR antiproliferative gene expression program.