International Journal of Cancer最新文献

Overcoming luminal breast cancer (BrCa) progression remains a critical challenge for improved overall patient survival. RUNX2 has emerged as a protein related to aggressiveness in triple-negative BrCa, however its role in luminal tumors remains elusive. We have previously shown that active FGFR2 (FGFR2-CA) contributes to increased tumor growth and that RUNX2 expression was high in hormone-independent mouse mammary carcinomas. To elucidate the interaction between FGFR2 and RUNX2 in human BrCa, we investigated their roles in tumor progression and treatment responsiveness. Increased FGFR2 activity resulted in higher RUNX2 expression, cell proliferation, and metastasis. In contrast, silencing FGFR2 reduced these parameters. Overexpression of RUNX2 in FGFR2-silenced cells rescued the inhibitory effects, promoting a more aggressive phenotype, even if compared with the wt RUNX2-transfected cells, which also had increased aggressiveness compared with naïve-transfected cells. RUNX2-overexpressing tumors were insensitive to endocrine- or FGFR inhibitor treatments. Notably, the CBFβ-RUNX complex inhibitor, AI-14-91, demonstrated great effectiveness in vitro. In a small cohort of luminal BrCa patients, nuclear RUNX2 expression was associated with tumor recurrence. Transcriptomic analysis strongly supported these data showing that patients with luminal carcinomas with high RUNX2 activity score have a worse progression-free interval than those with low RUNX2 activity. Our findings suggest a complex interplay between FGFR2 and RUNX2 in regulating tumor aggressiveness. This study underscores the significance of RUNX2 in luminal BrCa progression and posits RUNX2 as a promising therapeutic target and as a potential prognostic biomarker in luminal BrCa patients.

The comparative efficacy and safety of programmed death-ligand 1 (PD-L1) inhibitors versus programmed death protein 1 (PD-1) inhibitors in breast cancer treatment remain inconclusive, as no head-to-head randomized controlled trials (RCTs) conducted. This study aims to evaluate the efficacy and safety of PD-1/PD-L1 inhibitors as monotherapy or in combination with chemotherapy for breast cancer. A systematic review and meta-analysis were performed using major databases and oncology conference proceedings. The primary outcomes were overall survival (OS) for advanced breast cancer and pathological complete response (PCR) rate for early breast cancer. Secondary outcomes included progression-free survival (PFS) for advanced breast cancer and incidence of adverse events (AEs). Seventeen studies met the inclusion criteria, consisting of seven RCTs on early-stage and 10 on advanced breast cancer. For advanced breast cancer, PD-1/PD-L1 inhibitors modestly improved OS compared to chemotherapy, with no significant differences between PD-1 and PD-L1 inhibitors. PD-L1 inhibitors showed greater improvement in PFS compared to PD-1 inhibitors. The likelihood of AEs of any grade was higher with PD-L1 inhibitor treatment than with PD-1 inhibitor treatment. In early breast cancer, combining PD-1/PD-L1 inhibitors with chemotherapy inducing higher PCR rates than chemotherapy alone, with PD-1 inhibitors achieving better outcomes than PD-L1 inhibitors. PD-1 inhibitors were linked to slightly higher rates of grade >2 AEs compared to PD-L1 inhibitors. The findings indicate that PD-1 inhibitors may offer advantages for advanced breast cancer due to similar OS and a lower rate of AEs. For early breast cancer, PD-1 inhibitors are recommended given their superior PCR rates.

Neurologic immune-related adverse events (nirAEs) represent rare, yet severe side effects associated with immune checkpoint inhibitor (ICI) therapy. Given the absence of established diagnostic biomarkers for nirAEs, we aimed to evaluate the diagnostic utility of serum Neurofilament Light Chain (NfL) and Glial Fibrillary Acidic Protein (GFAP). Fifty-three patients were included at three comprehensive cancer centers, of these 20 patients with manifest nirAEs and 11 patients with irHypophysitis. Controls included patients without any irAE (n = 8) and other irAEs (n = 14). Using a single-molecule enzyme-linked immunosorbent assay (Simoa), serum levels were measured prior to, during and after the manifestation of (n)irAEs in 80 samples. Symptom severity of the (n)irAEs was graded according to the Common Criteria for Adverse Events (CTCAE) version 5.0. Serum NfL levels were significantly higher in the nirAE group (n = 20) compared to irHypophysitis (n = 11; p = .0025) and controls (n = 22; p = .0384). Subgroup analysis demonstrated a significant elevation of NfL in nirAEs of the peripheral nerves (PNirAE) in contrast to neuromuscular syndromes (NMirAE) (p = .0260). GFAP levels were highest in patients with nirAE affecting the central nervous system (CNSirAE) compared to PNirAE and NMirAE (p = .0064). Symptom severity of nirAEs was associated with increased levels of NfL and GFAP (p = .0069, .0092). Individuals with elevated NfL levels exhibited less favorable outcomes of the (n)irAEs (p = .0199). Measurement of NfL and GFAP may be helpful for the differentiation of the broad spectrum of nirAEs and may serve as an indicator of symptom severity. Further investigation is needed to evaluate their potential as diagnostic and prognostic biomarkers.

Kaposiform hemangioendothelioma (KHE) is a rare vascular tumor that typically presents in infancy or early childhood. As awareness of KHE increases, it is imperative that the management of KHE be updated to reflect the latest evidence-based guidelines. The aim of this study was to integrate the literature and Chinese expert opinions to provide updated recommendations that will guide the diagnosis, treatment, and prognosis of patients with KHE. According to this consensus statement, 28 nationally peer-recognized experts in vascular anomalies and an expert in evidence-based medicine were assembled and formed three consensus subgroups. A series of key themes and questions were developed for each group, including recommendations for diagnosis, treatment, and prognosis. A systematic search was conducted for English-language articles published in PubMed and other relevant studies identified by the expert panel. A diagnosis of KHE necessitates the integration of clinical, imaging, and histologic features. The treatment of KHE should be tailored to the specific characteristics of each patient, including the size of the lesion, the presence of symptoms, the location, and the overall condition of the patient. In addition to focusing on the disease itself, it is also important to consider the complications of KHE and their impact on prognosis. The recommendations presented herein are intended to assist in the guidance of clinical practice and decision-making in patients with KHE, with the objective of improving patient outcomes.

High-risk human papillomavirus (hrHPV) genotype is needed for adequate cervical cancer screening and HPV vaccination program evaluation as recommended by different guidelines. We aimed to assess the rate of HPV infection and HPV genotype distribution using vaginal self-sampling in a cohort of unscreened reproductive-age women in Ethiopia. A community-based cohort study was conducted with women aged 23-46 living in Adama, Ethiopia. A total of 885 self-collected vaginal swabs were obtained and tested for hrHPV genotypes with the real-time polymerase chain reaction technique. The overall hrHPV prevalence was 21.1% (187/885, 95% confidence interval [CI]: 18.5-24.0). Among women living with human immunodeficiency virus, 46% (30/56) (95% CI: 33.7-59) were hrHPV positive compared with 19% (157/820) (95% CI: 16.2-22) of human immunodeficiency virus-negative women. The most frequent genotypes were HPV16 (3.1%), HPV51 (3.1%), HPV35 (2.6%), HPV56 (2.6%), HPV52 (2.4%), HPV31 (2.5%), and HPV39 (2.5%). Among the 187 HPV-positive women in self-samples, HPV 16/18 was found in 21% (39), HPV 16/18/45 was found in 24% (44), and HPV 16/18/31/33/45/52/58 was prevalent in 56% (104). Out of 116 biopsies, 7% (8) had cervical intraepithelial lesions and worse identified. Of these eight cervical intraepithelial lesions and worse patients, only 25% tested positive for HPV-16; none tested positive for HPV-18 or 45. One out of five women tested positive for hrHPV genotypes. Other HPV genotypes not covered by the quadrivalent HPV vaccine but associated with clinically significant cervical high-grade lesions or cancer were detected in 75%. It is more effective to prevent cervical cancer by switching to the nine-valent HPV vaccine.

Human papillomavirus (HPV)-associated high-grade vulvar intraepithelial lesion (HSIL) is a precursor of vulvar squamous cell carcinoma (VSCC). Because of the 8% cancer risk, many vulvar HSIL patients undergo aggressive and mutilating treatments. Characterizing HSIL by their progression risk can help individualize treatment strategies. Accordingly, copy number alterations (CNAs) and DNA methylation have been identified as biomarkers for cancer risk stratification of HSIL. Here, we assessed their potential correlation, and relation to HPV16 (sub)lineages and progression to vulvar cancer. Eighty-two vulvar formalin-fixed paraffin-embedded (FFPE) samples, including controls, HSIL, HSIL adjacent to VSCC and VSCC, with previously determined DNA methylation profiles, were analysed for CNAs using mFAST-SeqS. Genome-wide z-scores were calculated to determine overall aneuploidy (aneuploidy scores), and compared to the methylation levels and status of marker panel ZNF582/SST/miR124-2. For 52 HPV16-positive cases, HPV (sub)lineages were determined by Sanger sequencing. HPV16 lineage A was predominant (86.4%), followed equally by lineages B, C, and D. Frequent chromosomal alterations included chr1pq, chr3q, chr9q gains, and chr2q, chr4q losses. Median aneuploidy scores increased across disease categories, from 0 in controls, to 3 in HSIL, 16 in HSIL adjacent to VSCC and 29 in VSCC. A positive relationship between aneuploidy scores and DNA methylation levels was found (ρ = 0.61, Spearman's rank correlation test). Aneuploidy scores were significantly higher in methylation-positive samples (p < .001). In conclusion, we showed that DNA methylation and CNAs both rise with increasing severity of disease, indicating their prognostic value for cancer risk stratification of HSIL, while no relation to HPV16 (sub)lineages was found.

Various birth characteristics may influence healthy childhood development, including the risk of developing childhood brain tumors (CBTs). In this study, we aimed to investigate the association between delivery methods, obstetric history, and birth anthropometrics with the risk of CBTs. This study used data from the Childhood Brain Tumour Epidemiology Study of Ontario (CBREO) which included children 0-15 years of age and newly diagnosed with CBTs from 1997 to 2003. Multivariable logistic regressions were performed to explore the association between delivery methods, obstetric history, and birth anthropometric variables, with subsequent CBT development. Models were adjusted for maternal and index child characteristics, and stratified by histology where sample size permitted. The use of assistive instruments (forceps or suction) during childbirth was significantly associated with overall CBTs (OR 1.84, 95% CI 1.30-2.61) and non-glial tumors (OR 2.57, 95% CI 1.60-4.13). Compared to first-born children, those second-born or greater had a lower risk of overall CBT development (OR 0.74, 95% CI 0.55-0.98), and glial histological subtype. All other birth characteristic variables explored were not associated with CBTs. The use of assistive devices such as forceps or suction during vaginal delivery carries potential risks, including increased risk of CBT development. There is an inverse association between birth order and CBTs, and future studies examining early childhood common infection may be warranted.

With the rise of anti-vascular endothelial growth factor antibody and programmed cell death-ligand 1 (PD-L1) regimens, particularly bevacizumab and atezolizumab, as first-line treatments for advanced hepatocellular carcinoma (HCC), there is a need to explore PD-L1 and programmed cell death 1 inhibitors in combination therapies for unresectable HCC (uHCC). Integrating systemic therapies with locoregional approaches is also emerging as a potent strategy. This study compares the outcomes of atezolizumab (PD-L1 inhibitor) and sintilimab (programmed cell death 1 inhibitor) with bevacizumab or its biosimilar, combined with hepatic arterial interventional therapies (HAIT) in uHCC patients. From January 2020 to September 2023, a retrospective analysis was conducted on 138 uHCC patients at Sun Yat-sen University Cancer Center. The cohort included 69 patients treated with atezolizumab with bevacizumab (Bev/Ate) and 69 with bevacizumab biosimilar with sintilimab (Bio/Sin), combined with HAIT. The propensity score matching was also employed to further explore the efficacy and safety. The median progression-free survival (mPFS) was 13.8 months for the Bev/Ate group and 10.0 months for the Bio/Sin group (p = 0.188). The Bev/Ate group showed significantly longer intrahepatic mPFS (HR 0.381; 95% confidence interval 0.176-0.824; p = .018) and higher overall response rates compared with the Bio/Sin group (60.87% vs. 31.88%, p = .001; 69.57% vs. 49.28%, p = .024) based on Response Evaluation Criteria in Solid Tumors v1.1 and modified Response Evaluation Criteria in Solid Tumors criteria. Treatment-related adverse events were similar between groups (p > .050). Combining atezolizumab or sintilimab with bevacizumab or its biosimilar alongside HAIT provided similar overall PFS in uHCC patients. However, the atezolizumab-bevacizumab combination with HAIT showed superior intrahepatic PFS and control rates, warranting further validation.