International Journal of Cancer最新文献

Filamin A (FLNA) is poorly expressed in adrenocortical carcinomas (ACC) compared to adenomas (ACA). Its presence is associated to a less aggressive tumour behaviour, potentially due to its role in negatively regulating IGF1R signalling. Upregulation of G2/M Wee1 kinase was shown in FLNA-deficient mouse neural progenitor cells, and it has been reported in several tumours. This study explored Wee1 expression in ACC and its regulation by FLNA, the effects of Wee1 inhibitor AZD1775, and the impact of FLNA on its efficacy in ACC cell lines and primary cells. Analysis of FLNA and Wee1 proteins revealed elevated Wee1 and reduced FLNA in ACC compared to normal adrenal gland. FLNA knockdown increased Wee1 protein in NCI-H295R, MUC-1, and in primary ACC cells. Higher p-CDK1 and cyclin B1 were shown in FLNA-silenced MUC-1, while decreased Wee1, p-CDK1 and cyclin B1 resulted after FLNA overexpression. Wee1 reduction was reverted by lactacystin treatment and FLNA transfection increased p-Wee1 (Ser123), suggesting FLNA's role in targeting Wee1 for degradation. AZD1775 dose-dependently reduced proliferation and viability in ACC cell lines and primary cultures, and it triggered MUC-1 cell death. Similar effects were induced by Wee1 silencing. FLNA depletion augmented AZD1775's efficacy in reducing proliferation and potentiating apoptosis in MUC-1 and primary cells. In conclusion, we demonstrated that FLNA regulates Wee1 expression by promoting its degradation, suggesting that low FLNA typical of ACC leads to increased Wee1 with consequent cancer cells growth. It proposes Wee1 inhibition as a new potential therapeutic approach for ACC, particularly for those lacking FLNA.

Cancer care places a heavy economic burden on families and health systems, driven by high treatment costs, lengthy hospital stays, and the necessity for extensive travel to specialized facilities. To address this challenge, an integrated health care network (IHCN) was implemented for maintenance treatment in acute leukemia. The IHCN encompassed outpatient services provided by local physicians and synchronous telemedicine consultation with pediatric oncologists. This study included twenty-two pediatric patients (eleven [50.0%] females; twenty [90.9%] with B-ALL and two [9.1%] with AML). The IHCN was offered to all rural patients (n = 17) with a one-way driving distance more than 30 km, while urban patients (n = 5) received regular cancer care. Throughout the study, rural patients had a total of 510 routine clinical visits, with 367 (72%) conducted through the IHCN. Physical examinations revealed similar frequency of new abnormal findings for urban and rural patients (22.4% vs. 17.8%; p = .31). Laboratory tests indicated no significant difference in the frequency of abnormal values for various parameters between both groups. Similarly, there was no discrepancy of drug modifications or interruption in maintenance therapy between the two settings (p = .85). Moreover, patients' health-related quality of life remained within the normative range, and user satisfaction with the IHCN was notably high. The implementation of the IHCN resulted in savings of 70,158 km, 950 h of travel, and 12,277 kg CO₂ emissions. This pilot study underscores the efficacy of a telemedicine-based IHCN, ensuring safety, quality of care, cost reduction, and satisfaction for both families and health care providers in pediatric leukemia management.

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.

Optimizing the timing of radiotherapy and chemotherapy tailored to the body's biological clock (i.e., chronotherapy) might improve treatment efficacy and reduce side effects. This systematic review evaluated the effect of chrono-radiotherapy and chrono-chemotherapy on treatment efficacy, toxicity and adverse events in head and neck cancer (HNC) patients from prospective and retrospective studies published between the date of database inception until March 2024. The primary outcome measures for chrono-radiotherapy were treatment efficacy and incidence of grade ≥3 oral mucositis, and the main outcome measures for chrono-chemotherapy were objective response rate (ORR) and overall toxicity and adverse events. Of 7349 records identified, 22 studies with 3366 patients were included (chrono-radiotherapy = 9 and chrono-chemotherapy = 13). HNC patients who underwent chrono-radiotherapy had 31% less risk of developing severe oral mucositis (grade ≥3) compared to evening radiotherapy (risk ratio: 0.69, 95% CI: 0.53-0.90, p < 0.05). Further, HNC patients who underwent chrono-chemotherapy using platinum-based and antimetabolite agents had 73% less risk of lower ORR compared to nontime-stipulated chemotherapy (risk ratio: 0.27, 95% CI: 0.09-0.84, p < 0.05). In addition, HNC patients who underwent chrono-chemotherapy had 41% less risk of lower overall toxicity and adverse events in comparison to nontime-stipulated chemotherapy (risk ratio: 0.59, 95% CI: 0.47-0.72, p < 0.05). In conclusion, chrono-chemotherapy studies showed evidence of improved treatment efficacy, while in chrono-radiotherapy it was maintained. Chrono-radiotherapy and chrono-chemotherapy studies provide evidence of reduced toxicity and adverse events. However, optimized circadian-based multicentric clinical studies are needed to support chrono-radiotherapy and chrono-chemotherapy in managing HNC.

Prognostic value of T-cells between primary colorectal cancer (pCRC) and its paired synchronous and metachronous liver metastasis (LM) is underinvestigated and is the subject of the present study. We enrolled into this retrospective cohort study patients, who underwent resection of both pCRC and synchronous LM (N = 55) or metachronous LM (N = 44). After immunohistochemical staining for CD3+, CD8+, and CD45R0+ whole slides were scanned and T-cell densities were quantified using QuPath software in tumor center (TC), inner margin (IM), outer margin (OM), and peritumor zone (PT) of pCRC and LM. High densities of CD8+ T-cells in TC, OM and PT of synchronous LM were associated with longer disease-free survival (DFS). Greater densities of CD3+ T-cells in IM and PT and CD8+ T-cells in IM, OM and PT in synchronous LM over pCRC were associated with longer DFS. Greater densities of CD8+ T-cells in the TC and IM and CD3+ T-cells in the IM of pCRC were found in the metachronous over synchronous group. The first novel finding demonstrated that high density of CD8+ T cells in synchronous LM were associated with favorable outcome. The second finding of high CD8+ cell density in pCRC in metachronous over synchronous CRC may provide a mechanistic basis for the delay of metastatic spread. Both findings could be applied clinically with own reference values.

The cancer burden continues to escalate in China. This study was designed to quantify the burden of deaths attributable to modifiable risk factors for major cancers in China from 2012 to 2035, and to provide evidence-based recommendations for cancer management. Using nationally representative data on risk factors and cancer mortality, a comparative risk assessment approach was employed to calculate the temporal trend of population-attributable fractions (PAFs) for 15 modifiable risk factors associated with major cancers in China. The PAF for modifiable risk factors decreased from 64.5% (95% uncertainty interval [UI]: 46.2%-75.3%) in 2012 to 59.3% (95% UI: 40.6%-71.2%) in 2035. Attributable deaths increased from 1,309,990 (95% UI: 938,217-1,529,170) in 2012 to 1,313,418 (95% UI: 898,411-1,577,189) in 2035, while attributable disability-adjusted life years (DALYs) rose from 28,488,120 (95% UI: 20,471,859-33,308,237) to 33,017,705 (95% UI: 22,730,814-39,564,735). Between 2012 and 2035, the top three risk factors contributing to cancer burden shifted from smoking, insufficient fruit intake and particulate matter <2.5 μm in diameter (PM_2.5) exposure to smoking, physical inactivity, and inadequate fruit intake. Controlling modifiable risk factors at recommended levels by 2020 could have prevented around 890,000 deaths and 2.2 million DALYs by 2035. The proportion of cancer burden due to modifiable risk factors is projected to decrease, but the absolute number continues to rise. Adhering to an optimal lifestyle could prevent ~40% of cancer deaths by 2035. Key modifiable risk factors including smoking, physical inactivity, and insufficient intake of fruits require high attention.

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.

Optimal cardiac dose constraints in breast cancer (BC) patients undergoing postoperative intensity-modulated radiation therapy (IMRT) are unclear, although as low as possible is recommended. This trial proposes serial cardiac dose constraint to optimize cardiac safety. Postoperative BC patients eligible for anthracycline/taxanes-based chemotherapy or HER2-targeted therapy were randomized to cardiac safety arm with prespecified mean heart dose (MHD) (≤6 Gy), V30 (≤20%), and V10 (≤50%) constraints, or to a control arm with in-house protocol (mainly MHD ≤8 Gy). The primary endpoint was cumulative incidence of newly onset cardiac events within 1-year post-RT. An exploratory analysis examined the relationship between whole heart dose metrics and those of substructures. Of 199 participants, 93 were in the cardiac safety and 106 in the control arm. The cardiac safety group showed lower MHD, V10, and V30. The 1-year cardiac event incidence was slightly lower in the cardiac safety group (19.4%) compared to controls (24.9%). The LVEF and diastolic dysfunction rates were 0% and 5.4% in the study arm, and 1.9% and 8.8% in the control arm, respectively. The LAD, LV, and RV received the highest doses for left-sided patients. For right-sided patients, RA, RCA, and RV were most irradiated. The MHD, V10, and Dmax of heart significantly correlated with all substructure doses in either laterality. Our study supports the early cardiac safety profile using IMRT in BC patients receiving cardiac-toxic systemic therapy, with serial cardiac dose constraints. Combined constraints on MHD and dose-volume parameters are representative of the cardiac substructure dose.

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.