International Journal of Cancer最新文献

High-risk HPV (hrHPV)-based screening has led to many unnecessary colposcopy referrals, mainly because of direct referral after low-grade cytology (ASC-US/LSIL). DNA methylation and genotyping tests on ASC-US/LSIL samples have the potential to significantly improve the efficiency of screening. In this study, 12 triage strategies were constructed from FAM19A4/miR124-2 or ASCL1/LHX8 methylation, HPV16/18 or HPV16/18/31/33/45 genotyping and 1-year repeat cytology. The performance was evaluated on 215 hrHPV-positive ASC-US/LSIL samples from the IMPROVE trial (NTR5078). Performance was measured by colposcopy referral rate, positive predictive value (PPV) for detecting precancer (CIN3), and negative predictive value (NPV). To evaluate efficiency, strategies were ordered by the cumulative colposcopy referral rate after 1-year cytology and compared by the marginal PPV to detect one additional CIN3 (mPPV). The most conservative strategy (referral when HPV16/18 and FAM19A4/miR124 methylation results are positive) had a direct referral rate of 5.2%, a cumulative referral rate after 1-year cytology of 54.1%, and mPPV of 19.3%. Replacing HPV16/18 by HPV16/18/31/33/45 increased the cumulative 1-year referral rate to 54.6%, and yielded an mPPV of 10.0%. Similar results were obtained for strategies with ASCL1/LHX8 methylation. Of all strategies, referral after an HPV16/18/31/33/45 positive, ASCL1/LHX8 methylation-positive, and/or 1-year cytology-positive result yielded the highest direct and cumulative 1-year colposcopy referral rates of 64.4% and 79.1%, respectively. The NPVs after 1-year cytology varied between 98.1% and 99.4%, warranting a return to routine screening. Altogether, DNA methylation-based triage strategies are recommended as they are discriminative for CIN3 and control the number of immediate colposcopy referrals.

Breast cancer is the most common cancer among women. Among them, human epidermal growth factor receptor-positive (HER2+) breast cancer is more malignant. Fortunately, many anti-HER2 drugs are currently used in clinical treatments to increase patient survival. However, some HER2+ patients (~15%) still develop drug resistance after receiving trastuzumab treatment, leading to treatment failure. Using CCLE and METABRIC database analyses, we found that fibroblast growth factor receptor 4 (FGFR4) mRNA was highly detected in tumors from HER2+ breast cancer patients (p < .001) and was associated with poorer survival in breast cancer patients. Through retrospective immunohistochemical staining analysis, we detected higher expression of FGFR4 protein in breast cancer tissues collected from patients who were resistant to trastuzumab therapy compared with breast cancer patients who responded to treatment. An FGFR4 inhibitor (FGF401) effectively inhibits tumor growth in trastuzumab-insensitive patient-derived xenograft (PDX) tumor-bearing mice. For molecular mechanism studies, we demonstrated that HER2/FGFR4 protein complexes were detected on the cell membrane of the tumor tissues in these trastuzumab-insensitive PDX tumor tissues. After trastuzumab treatment in these drug-resistant breast cancer cells, FGFR4 translocates and enters the nucleus. However, trastuzumab-induced nuclear translocation of FGFR4/HER2-intracellular domain protein complex in trastuzumab-resistant cancer cells is blocked by FGF401 treatment. We believe that FGFR4 overexpression and complex formation with HER2 can serve as molecular markers to assist clinicians in identifying trastuzumab-resistant tumors. Our results suggest that FGF401 combined with trastuzumab as adjuvant therapy for patients with trastuzumab-resistant breast cancer may be a potential new treatment strategy.

Cerebrovascular events (CVEs) are serious late adverse events among childhood cancer survivors. We estimated the incidence and risk factors of symptomatic CVEs and described the clinical characteristics among childhood cancer survivors after upper body radiotherapy. The Dutch Childhood Cancer Survivor Study LATER cohort study includes 5-year childhood cancer survivors diagnosed 50 Gy was associated with 6-fold increased risk, compared to upper body radiotherapy not involving the cranium (hazard ratio = 6.3, 95%CI: 3.3-12.1). In a subgroup with available data on lifestyle and comorbidities, hypertension (odds ratio[OR] = 6.2, 95%CI: 1.6-23.8) and obesity (BMI≥30 vs. <30 = 2.95, 95%CI: 1.1-8.0) significantly increased CVE risk. During CVE episode, 17 (16%) had a life-threatening situation, and two (2%) others died. In 28%, a second CVE developed during follow-up. At end of follow-up, 29% were deceased, and 40% of those alive were unable to carry out normal activities/active work. Childhood cancer survivors treated with higher doses of cranial radiotherapy are at highest risk for developing CVEs. CVEs occur at a young age and cause a high morbidity. Studies to investigate risk-reducing secondary preventive interventions are warranted.

Smokeless tobacco (SLT) use is an established carcinogen to the nasal cavity, lip, and oropharynx, however, few studies have examined cancer risks in older African women among whom SLT use is common. We investigated snuff use and the risk of site-specific cancers among 15,336 newly diagnosed female cancer patients in the Johannesburg Cancer Study, South Africa. We designed case-control comparisons across multiple cancer outcomes: (a) known SLT-associated cancers; (b) other tobacco-related cancers and (c) genital cancers owing to intravaginal snuff use. Controls (n = 2961) comprised all other cancer patients. We also investigated (d) each control cancer type versus the remaining controls to explore possible associations with other cancers. Logistic models were fitted to estimate odds ratios adjusted for age, education, tobacco smoking, alcohol, HIV, and language. Overall, ever use of snuff was 22% among control cancers. Ever snuff use was associated with cervical (OR 1.14 [95%CI 1.00-1.30]) and eye and adnexa cancer (OR 1.95 [95%CI 1.03-3.70]). Associations with vulva cancer were less clear, 95% CI's for the main effects included 1 but a subgroup analysis restricted to never-smokers of current-versus-never users was positive (OR 2.10 [95%CI 1.25-3.50]). Surprisingly SLT users have lower risks of stomach cancer (OR 0.60 [95%CI 0.37-0.99]) and Hodgkin Lymphoma (OR 0.48 [95%CI 0.23-0.97]). Snuff use may increase the risk for cervical and vulva cancer in women, which is plausible via intravaginal use. Further research on the impact of SLT on female genital cancers with more detailed exposure data, including timing, intensity, and routes of use are required.

This prospective, two-cohort phase 2 trial with random allocation was conducted to evaluate the safety and efficacy of neoadjuvant tislelizumab combined with nab-paclitaxel/paclitaxel and cisplatin (TP) in patients with esophageal squamous cell carcinoma (ESCC). Patients were enrolled and randomly assigned to the nab-paclitaxel or paclitaxel cohorts at a 1:1 ratio, and received intravenous tislelizumab (200 mg, day 1) combined with cisplatin (25 mg/m², days 1–3) and either nab-paclitaxel (125 mg/m², days 1 and 8) or paclitaxel (150 mg/m², day 1) in a 21-day cycle for two cycles before surgery. The primary endpoint was the major pathological response (MPR) rate. From March 01, 2022 to April 10, 2023, 46 patients were enrolled (n = 23 in each cohort), with 42 patients receiving the full two-cycle treatments and undergoing surgery (n = 22 in the nab-paclitaxel cohort, n = 20 in the paclitaxel cohort). The MPR rate and the pCR rate in the total cohort were 44.2% (19/42) and 19.0% (8/42), respectively, with 59.1% (13/22) and 31.8% (7/22) in the nab-paclitaxel cohort and 30.0% (6/20) and 5.0% (1/20) in paclitaxel cohorts. The most common treatment-related adverse events (TRAEs) were anemia (89.1%) and alopecia (71.7%), and no significant difference in TRAEs was observed between the two cohorts. Up until March 28, 2024, the median follow-up time was 15.5 months (range of 6.0–24.3 months), and the survival analysis revealed that the patients in the nab-paclitaxel cohort had a higher event-free survival (p = .002). In conclusion, neoadjuvant tislelizumab combined with cisplatin and nab-paclitaxel, rather than cisplatin and paclitaxel, is a more effective neoadjuvant strategy for locally advanced thoracic ESCC.

Data investigating the natural history of high-risk human papillomavirus (HR-HPV) infection in mid-adult women compared with young adult women from regions exhibiting a bimodal distribution pattern are scarce. From November 2012 to September 2019, 3681 healthy women aged 18–45 years from the control group of a bivalent HPV vaccine Phase 3 trial in China were followed over 5.5 years. At scheduled visits (Day 0, months 7, 12, 18, 24, 30, 42, 54, and 66), cervical samples were collected for ThinPrep Pap tests and HPV DNA testing, women with abnormal cytology were referred for colposcopy. Data was analyzed using Cox regression model and a competing risk model. Sensitivity analyses were performed among participants attending all scheduled visits. The incidences of HR-HPV persistent infections (over 6 months [6mPIs]) were 35.5 and 29.0 per 1000 person-years (PYs) (hazard ratio [HR] = 1.21, 95% confidence interval [CI]: 1.00, 1.46), and HR-HPV associated CIN grade 2 or greater (CIN2+) were 4.3 and 1.9 per 1000 PYs (HR = 2.31, 95% CI: 1.25, 4.26) in women aged 18–26 and 27–45 years. Competing risk models showed that the cumulative incidence of HR-HPV infections that progressed to CIN2+ was significantly higher in women aged 18–26 than in women aged 27–45 (5.3% vs. 2.9%, Gray's test p = .0291). The cumulative clearance rates of HR-HPV infections in women aged 18–26 and 27–45 were similar (94.7% vs. 95.8%, Gray's test p = .3309) during the study period. In conclusion, although mid-adult women exhibit lower incidences of HR-HPV infection and associated cervical lesions compared to young women, this population continues to face a substantial risk of acquiring causal HPV infections, which may progress to cervical lesion.

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.

The most common somatic alteration in primary prostate cancer is the TMPRSS2:ERG gene fusion, which may be caused or promoted by distinct etiologic factors. The objective of this systematic review was to assess epidemiologic evidence on etiologic factors for prostate cancer by tumor TMPRSS2:ERG fusion status in human populations. Of 3071 publications identified, 19 cohort or case-control studies from six distinct study populations were included in this systematic review. Etiologic factors included germline genetic variants, circulating hormones, and dietary and lifestyle factors. Taller height, higher total and free testosterone levels, and fewer trinucleotide repeats in AR were possibly associated with higher risk of TMPRSS2:ERG-positive prostate cancer. Excess body weight, greater vigorous physical activity, higher lycopene intake, and the use of calcium channel blockers were associated with lower risk of TMPRSS2:ERG-positive prostate cancer. Diabetes and family history of prostate cancer were associated with both TMPRSS2:ERG-positive and TMPRSS2:ERG-negative prostate cancer. Prostate cancer germline variants had suggestive differential associations with TMPRSS2:ERG-positive or TMPRSS2:ERG-negative prostate cancer. However, results were based on few distinct study populations and generally had low precision, underscoring the need for replication. In conclusion, prostate cancer with TMPRSS2:ERG fusion is an etiologically distinct subtype that may be, in part, preventable by addressing modifiable and hormonally acting etiologic factors that align with the established mechanistic role of TMPRSS2:ERG in androgen, insulin, antioxidant, and growth factor pathways.

One of the aspects of tumor metabolism that distinguish it from healthy tissue is the phosphorylation of choline by choline kinases, which initiates the synthesis of phosphatidylcholine. Presently, there is a lack of comprehensive reviews discussing the current understanding of the role of choline kinase in cancer processes, as well as studies on the anti-tumor properties of choline kinase inhibitors. To address these gaps, this review delves into the enzymatic and non-enzymatic properties of CHKα and CHKβ and explores their precise involvement in cancer processes, particularly cancer cell proliferation. Additionally, we discuss clinical aspects of choline kinases in various tumor types, including pancreatic ductal adenocarcinoma, ovarian cancer, lung adenocarcinoma, lymphoma, leukemia, hepatocellular carcinoma, colon adenocarcinoma, and breast cancer. We examine the potential of CHKα inhibitors as anti-tumor drugs, although they are not yet in the clinical trial phase. Finally, the paper also touches upon the significance of choline kinases in non-cancerous diseases.

Glucocorticoids (GCs), commonly used for anti-inflammatory and cancer treatments, have been linked to the promotion of cancer metastasis. Yet, the molecular mechanisms behind this potential remain poorly understood. Clarifying these mechanisms is crucial for a nuanced understanding and potential refinement of GC therapies in the context of cancer treatment. In HEK293T cells, co-immunoprecipitation (Co-IP) and chromatin immunoprecipitation sequencing (ChIP-seq) were used with antibodies of glucocorticoid receptor (GR) and ten-eleven translocation enzymes (TET) family proteins (TET1, TET2, TET3). Drug repositioning was performed through the Connectivity Map database, using common target genes of GR and TET2 in HEK293 and HCT116 cell lines and differentially expressed genes (DEGs) of colorectal cancer (CRC). Cell migration and invasion were tested in CRC cell lines with varying GR expression, that is, HCT116 and HT29 cell lines. Dexamethasone (Dex) treatment resulted in a significant difference in cell migration rates in two CRC cell lines with disparate GR expression levels. Co-IP and ChIP-seq analyses substantiated the interaction between GR and TET family proteins in HEK293T cells. Belinostat, the selected compound, was successfully validated for its potential to counteract the effects of GC-induced invasion in CRC cells in vitro. Transcriptomic analyses of Belinostat-treated HCT116 cells revealed down-regulation of target genes associated with cancer metastasis. This study provides valuable insights into the molecular mechanisms underlying GC-induced metastasis, introducing newly repositioned compounds that could serve as potential adjuvant therapy to GC treatment. Furthermore, it opens avenues for exploring novel drug candidates for CRC treatment.