Wiley最新文献

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.

Incorporating susceptibility genetic variants of risk factors has been reported to enhance the risk prediction of polygenic risk score (PRS). However, it remains unclear whether this approach is effective for lung cancer. Hence, we aimed to construct a meta polygenic risk score (metaPRS) of lung cancer and assess its prediction of lung cancer risk and implication for risk stratification. Here, a total of 2180 genetic variants were used to develop nine PRSs for lung cancer, three PRSs for different histopathologic subtypes, and 17 PRSs for lung cancer-related risk factors, respectively. These PRSs were then integrated into a metaPRS for lung cancer using the elastic-net Cox regression model in the UK Biobank (N = 442,508). Furthermore, the predictive effects of the metaPRS were assessed in the prostate, lung, colorectal, and ovarian (PLCO) cancer screening trial (N = 108,665). The metaPRS was associated with lung cancer risk with a hazard ratio of 1.33 (95% confidence interval: 1.27-1.39) per standard deviation increased. The metaPRS showed the highest C-index (0.580) compared with the previous nine PRSs (C-index: 0.513-0.564) in PLCO. Besides, smokers in the intermediate risk group predicted by the clinical risk model (1.34%-1.51%) with the intermediate-high genetic risk had a 6-year average absolute lung cancer risk that exceeded the clinical risk model threshold (≥1.51%). The addition of metaPRS to the clinical risk model showed continuous net reclassification improvement (continuous NRI = 6.50%) in PLCO. These findings suggest the metaPRS can improve the predictive efficiency of lung cancer compared with the previous PRSs and refine risk stratification for lung cancer.

Hematologic adverse events (AEs) are common and serious toxicities in patients with hematologic malignancies undergoing blinatumomab therapy. However, restrictive selection criteria in pivotal clinical trials can lead to an underestimation of rare but fatal toxicities. In this study, we systematically analyzed hematologic AEs associated with blinatumomab using the Food and Drug Administration Adverse Event Reporting System (FAERS) from October 2014 to December 2023. Disproportionate analysis was performed to identify overreported AEs, with a reporting odds ratio (ROR), and a lower bound of the 95% confidence interval (ROR₀₂₅) exceeding one considered significant. Additionally, adjusted mortality rates and risk ratios (RR) of the top 10 reported hematologic AEs were calculated using a logistic regression model. Among 4745 blinatumomab-related cases, 418 (8.81%) involved hematologic AEs. We identified 22 significantly overreporting hematologic AEs compared to the full database, with myelosuppression (n = 39 [9.33%], ROR₀₂₅ = 8.04), disseminated intravascular coagulation (DIC, n = 31 [7.42%], ROR₀₂₅ = 15.14), and bone marrow failure (n = 14 [3.35%], ROR₀₂₅ = 3.41) notably underestimated in clinical trials. DIC resulted in a substantial mortality rate of 45.16%. Finally, DIC was found to be independently associated with death in a multivariable logistic regression analysis (RR = 2.47 [95% CI: 1.11-3.83]). These findings could aid clinicians in the early detection of these rarely reported but fatal hematologic AEs, thereby reducing the risk of severe toxicities in blinatumomab recipients.

The potential impact of concomitant medications such as systemic antibiotics, proton pump inhibitors (PPIs), and probiotics in patients with extensive-stage small cell lung cancer (ES-SCLC) receiving first-line chemo-immunotherapy combinations remains unclear. We ran a post hoc analysis of the IMpower133 phase I/III trial, which randomized patients with ES-SCLC to receive carboplatin/etoposide with either atezolizumab or placebo for 4 cycles, followed by maintenance therapy. We included any systemic antibiotic/probiotic exposure within 42 days prior to treatment initiation and any PPIs treatment within 30 days prior to treatment initiation. We explored the potential prognostic impact of antibiotics, PPIs and probiotics across the atezolizumab/chemotherapy and placebo/chemotherapy arms including the multivariable interaction term between the treatment modality and antibiotics/PPIs/probiotics. The analysis included 198 patients in the atezolizumab/chemotherapy arm and 195 in the placebo/chemotherapy arm. Baseline clinic-pathologic features were well balanced between the two cohorts, with 17 (8.6%) and 14 (7.2%) patients on antibiotics, 43 (21.7%) and 55 (28.2%) on PPIs, and 3 (1.5%) and 5 (2.6%) on probiotics among the atezolizumab/chemotherapy and placebo/chemotherapy cohorts, respectively. Exposure to antibiotics, PPIs, or probiotics was not associated with overall survival or progression free survival in either cohort. Furthermore, interaction terms between these medications and treatment modalities were not statistically significant. Baseline use of antibiotics, PPIs or probiotics did not influence clinical outcomes in patients with ES-SCLC treated with first-line atezolizumab/placebo plus chemotherapy, suggesting that they may not have a notable impact on clinical outcomes and could be considered for use in this patient population when necessary.

Gastroenteropancreatic neuroendocrine tumours (GEP-NETs), which may be hormone secreting (e.g., gastrinomas and insulinomas) or non-secreting (also known as non-functioning NETs) are associated with severe morbidity and have a median overall survival of 75-124 months. Studies have highlighted the importance of epigenetic mechanisms in GEP-NETs pathogenesis, with the most frequently mutated genes being the epigenetic regulators, MEN1, DAXX, and ATRX. However, the consequences of these aberrant epigenetic mechanisms are poorly understood. The calcium sensing receptor (CASR), a G protein coupled-receptor, is epigenetically silenced in cancers, and therefore we examined its role in GEP-NET subtypes. Using RNA-Scope and quantitative PCR analyses in two independent tumour cohorts from Europe (n = 18 patients) and the USA (n = 46 patients) we showed that CASR mRNA is almost completely absent in gastrinomas, insulinomas and non-functioning pancreatic NETs. Furthermore, immunohistochemical staining confirmed a significant reduction in CaSR protein expression in all GEP-NET subtypes, compared to normal islets. DNA methylationEPIC and ATAC-seq analyses in the pancreatic NET cell line QGP-1 showed the CaSR promoter was both hypermethylated and in a region of closed chromatin. Furthermore, transfection of wild type CaSR into QGP-1 cells decreased cell viability, in keeping with the CaSR having a role in cellular proliferation. In summary, our study reveals that CaSR expression is decreased in GEP-NETs and that this reduced expression is likely due to DNA methylation and chromatin changes. Moreover, we demonstrate that transfection of the CaSR into a PNET cell line reduces cell viability, thereby indicating that the CaSR acts as a tumour suppressor in this tumour type.

Although significant progress in the treatment of breast cancer has been achieved, toxic therapies would not be required if breast cancer could be prevented from developing in the first place. While breast cancer prevention is difficult to study in humans due to long disease latency and stochastic cancer development, transgenic mouse models with 100% incidence and defined mammary tumor onset, provide excellent models for tumor prevention studies. In this study, we used Neu/Erbb2 transgenic mice (MTB-TAN) as a model of human HER2⁺ breast cancer to investigate whether a family of microRNAs, known as the miR-200 family, can prevent mammary tumor development. Overexpression of Neu induced palpable mammary tumors in 100% of the mice within 38 days of Neu overexpression. When the miR-200b/200a/429 cluster was co-overexpressed with Neu in the same mammary epithelial cells (MTB-TANba429 mice), the miR-200b/200a/429 cluster prevented Neu from inducing mammary epithelial hyperplasia and mammary tumor development. RNA sequencing revealed alterations in the extracellular matrix of the mammary gland and a decrease in stromal cells including myoepithelial cells in Neu transgenic mice. Immunohistochemistry for smooth muscle actin confirmed that mammary epithelial cells in control and MTB-TANba429 mice were surrounded by a layer of myoepithelial cells and these myoepithelial cells were lost in MTB-TAN mice with hyperplasia. Thus, we have shown for the first time that elevated expression of miR-200 family members in mammary epithelial cells can completely prevent mammary tumor development in Neu transgenic mice possibly through regulating myoepithelial cells.

Experimental research has uncovered lipocalin 2 (LCN2) as a novel biomarker implicated in the modulation of intestinal inflammation, metabolic homeostasis, and colon carcinogenesis. However, evidence from human research has been scant. We, therefore, explored the association of pre-diagnostic circulating LCN2 concentrations with incident colorectal cancer (CRC) in a nested case-control study within the in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. LCN2 was measured in 1267 incident CRC cases matched to 1267 controls using incidence density sampling. Conditional logistic regression was used to estimate incidence rate ratios (IRRs) and 95% confidence intervals (95% CIs) according to tumor subsite and sex. Weighted Cox proportional hazard regression was used to explore associations by adiposity status. In multivariable-adjusted analyses, the IRR [95% CI] per doubling in LCN2 concentration was 1.16 [0.98-1.37] for CRC overall, 1.26 [1.00-1.59] for colon cancer, and 1.08 [0.85-1.38] for rectal cancer. The association for colon cancer was more pronounced in women (IRR [95% CI], 1.66 [1.20-2.30]) and for proximal colon cancer (IRR [95% CI], 1.96 [1.15-3.34]), whereas no association was seen in men and distal colon cancer. The association for colon cancer was positive in individuals with high waist circumference (hazard ratio [95% CI], 1.69 [1.52-1.88]) and inverse in individuals with low waist circumference (hazard ratio [95% CI], 0.86 [0.76-0.98], P interaction<0.01). Overall, these data suggest that pre-diagnostic LCN2 concentrations were positively associated with colon cancer, particularly occurring in the proximal colon, in women and among individuals with abdominal adiposity.

The burden of uterine cancer is growing and, in the US and UK, mortality rates are poorest among black women. Early detection of these cancers is critical and poor performance of ultrasound in black women may contribute to adverse outcomes. Limited data on this topic are available from Africa. We assessed whether a simple DNA methylation test, the WID-qEC, enables detection of all epithelial uterine (endometrial and cervical) cancers in women presenting with abnormal uterine bleeding (AUB) in Ghana. Among 118 women ≥40 years presenting with AUB, 106 consented to the study and a cervicovaginal sample was obtained for WID-qEC testing. Subsequent to ultrasound assessment 102 women had a cervical or endometrial biopsy. Histopathology, ultrasound and WID-qEC testing were analyzed and compared. Among the 102 volunteers, 8 and 15 were diagnosed with endometrial and cervical cancer (EC and CC), respectively. The receiver operating characteristic (ROC) area under the curve (AUC) was 0.56 (95% confidence interval [CI] 0.25-0.86) for sonographic endometrial thickness (ET) and 0.98 (95% CI 0.94-1.00) for the WID-qEC test. Sensitivity and specificity of the prespecified ET ≥5 mm were 66.7% (95% CI 24.1-94.0) and 22.7 (95% CI 12.0-38.2) and for the prespecified WID-qEC SUM-PMR ≥ 0.3 were 100% (95% CI 56.1-100.0) and 76.1 (96%CI 60.9-86.9), respectively. In addition, 15 CCs were detected by the WID-qEC test [sensitivity 100% (95% CI 74.7-100.0)]. The WID-qEC test accurately detects both EC and CC in black women presenting with AUB.

Brainstem gliomas (BSGs) are a class of clinically refractory malignant tumors for which there is no uniform and effective treatment protocol. Ultrasound and radiation can activate hematoporphyrin and produce sonodynamic and radiodynamic effects to kill cancer cells. Therefore, we conducted the first phase I clinical trial of sonodynamic therapy (SDT) combined with radiotherapy (RT) for the treatment of BSGs to verify its safety and efficacy. We conducted a study of SDT combined with RT in 11 patients with BSGs who received SDT and RT after hematoporphyrin administration. Magnetic resonance imaging was performed during this period to assess the tumor, and adverse events were recorded. All adverse events recorded were grade 1-2; no grade 3 or more serious adverse events were observed. Treatment was well tolerated, and no dose-limiting toxicities were observed. There were no treatment-related deaths during the course of treatment. 8 of 11 patients (72.7%) maintained stable disease, 2 (18.2%) achieved partial response, and the tumors were still shrinking as of the last follow-up date. The median progression-free survival (PFS) for patients was 9.2 (95% confidence interval [CI] 6.2-12.2) months, and the median overall survival (OS) was 11.7 (95% CI 9.6-13.8) months. Therefore, SDT combined with RT has a favorable safety and feasibility and shows a preliminary high therapeutic potential.

Patients with head and neck squamous cell carcinoma (HNSCC) who have progressed following primary treatment (PT) have a poor prognosis. In this group, nivolumab has been demonstrated to significantly improve outcomes. This study presents the efficacy of nivolumab in Polish patients with recurrent and/or metastatic (R/M) HNSCC using real-world data. The analyzed group consisted of 324 adult patients with R/M HNSCC following platinum-based therapy. Patients were divided into 3 groups based on the time from completion of PT to nivolumab initiation (tPT-N): within 6 months (refractory), between 6 and 24 months (sensitive, tPT-N ≤24), and beyond 24 months (sensitive, tPT-N >24). Survival analysis and the Cox proportional hazards model were performed to evaluate how various risk factors affect patient outcomes. The 1-year and 2-year overall survival (OS) was 19.1%, 6.1%, 30.7%, 9.4%, and 45.7%, 29.1% in refractory, sensitive tPT-N ≤24, sensitive tPT-N >24 patients, respectively and was higher for both sensitivity groups vs. refractory (p = .004) and for sensitive tPT-N >24 versus refractory and sensitive tPT-N ≤24 (p <.001). Patients with nasopharyngeal cancer had OS significantly higher than patients with other primary tumor localization. The multivariate Cox analysis showed a significant favorable effect of tPT-N >24 (HR = 0.53, p = .001) and nasopharyngeal cancer on OS (HR = 0.20, p = .008). Conversely, female sex was identified as an unfavorable factor for OS (HR = 1.48, p = .020). In our study, we established that the benefit of nivolumab increases with the increasing tPT-N. The probability of death is significantly lower in male patients and patients with nasopharyngeal cancer regardless of tPT-N.