International Journal of Cancer最新文献

Given that body mass index (BMI) fails to distinguish between fat and muscle, and that the relationship between body composition and colorectal cancer (CRC) risk in the Chinese population is insufficiently understood, we prospectively examined the associations between predicted body compositions and CRC risk in a large cohort. Cox proportional hazards regression models were used to evaluate hazard ratios (HRs) and 95% confidence intervals (CIs) for the relationships between predicted body compositions and CRC risk. Over a mean follow-up period of 14.88 years, we observed 825 incident cases of CRC. To address potential reverse causation, we additionally fitted lagged Cox models with delayed entry at 2 and 4 years after baseline. In multivariable-adjusted models, individuals in the fourth and fifth quintiles of predicted fat mass exhibited HRs of 1.31 (95% CI 1.04-1.64) and 1.38 (95% CI 1.10-1.73), respectively, compared with those in the first quintile. Predicted body fat percentage and BMI showed similar positive associations with CRC risk, whereas predicted lean body mass was not significantly associated; these associations were broadly similar in the 4-year lag analysis. Restricted cubic spline models revealed positive dose-response associations between these predicted fat mass, body fat percentage, and BMI, and CRC risk, with evidence of non-linearity for predicted fat mass. Elevated levels of predicted fat mass, predicted body fat percentage, and BMI were associated with an increased risk of CRC in this Chinese cohort.

The investigation of peripheral neurotoxicity associated with systemic anticancer therapy (SACT) agents is often confined to a small range of chemotherapy agents. This study aimed to identify all SACT agents associated with peripheral neurotoxicity and, specifically, peripheral neuropathy, and to provide incidence estimates for the development of each type of neurotoxicity associated with each agent. Antineoplastic agents approved globally for clinical and/or research purposes were identified through triangulation of nine national and global drug product databases. The class of each agent was identified using DrugBank Online. Evidence of peripheral neurotoxicity and, specifically, peripheral neuropathy was obtained by reviewing Micromedex (and, where required, supplemented by data reported in national clinical trials registries). A total of 467 approved antineoplastic agents were identified for clinical and/or research purposes globally. Peripheral neurotoxicity (including neuropathy) was associated with 144 (31%) agents: 49 (45%) classical chemotherapeutic agents; 61 (21%) targeted therapies; 26 (63%) immunotherapies; and 8 (25%) hormone therapies. Peripheral neuropathy, specifically, was associated with 77 (16%) agents: 30 (27%) classical chemotherapeutic agents; 31 (11%) targeted therapies; 16 (39%) immunotherapies; and no hormone therapies. Based on the currently available evidence, this inventory of neurotoxic SACT agents could be considered exhaustive. From clinical and research perspectives, a comprehensive inventory of neurotoxic SACT agents is pivotal to informing drug design and understanding and implementing appropriate drug choice, as well as investigating the mechanisms involved in the neurotoxic effects of agents and identifying neuroprotective strategies for patients undergoing SACT.

We aimed to evaluate the long-term tamoxifen benefit by progesterone receptor (PR) levels in postmenopausal lymph node-negative breast cancer patients with estrogen receptor (ER)-positive/human epidermal growth factor receptor 2-negative (HER2) tumors in the STO-3 randomized trial. This is a secondary analysis of the STO-3 trial including 559 postmenopausal breast cancer patients by PR levels. Patients were randomly assigned to at least 2 years of adjuvant tamoxifen therapy (40 mg once daily) versus no endocrine therapy in the Stockholm (STO)-3 trial. Twenty-five-year distant recurrence-free interval (DRFI) was assessed by Kaplan-Meier, multivariable Cox proportional hazard regression, and multivariable time-varying analyses. Univariable Kaplan-Meier analysis showed a significant long-term tamoxifen benefit for PR-positive disease using a threshold of 10% or greater (DRFI, tamoxifen treated 85% vs. control 68%; p < .0001). Similarly, patients with high PR gene expressing tumors had a significant long-term tamoxifen therapy benefit (DRFI, tamoxifen treated 84% vs. control 66%; log-rank p < .001). In contrast, we report no significant therapy benefit for patients with PR-negative disease (DRFI, tamoxifen treated 79% vs. control 70%; log-rank p = .14) or low PR gene expression (DRFI, tamoxifen treated 82% vs. control 74%; log-rank p = .17). Multivariable Cox proportional hazard regression modelling confirmed the univariable findings for PR-positive disease (HR = 0.37; 95% CI [0.23-0.61]). Time-varying analysis revealed a treatment benefit for PR-positive disease up to 25 years (HR = 0.35; 95% CI [0.16-0.79]), but not for patients with PR-negative tumors. PR-positivity as determined by immunohistochemistry predicted long-term benefit from adjuvant tamoxifen in lymph node-negative postmenopausal breast cancer patients with ER+/HER2- tumors.

Esophageal adenocarcinoma (EAC) demonstrates poor survival rates despite multimodal treatments, with significant inter-patient variability in response to standard pre-/perioperative therapies. This study investigates the relationship between adherens junction (AJ) protein expression in pre-treatment biopsies and response to neoadjuvant therapies in EAC. Mass spectrometry-based proteomics was performed on diagnostic biopsies from 157 EAC patients who subsequently received either perioperative FLOT chemotherapy or neoadjuvant CROSS radiochemotherapy. Protein expression profiles were analyzed with emphasis on AJ components. Findings were correlated with treatment response and histopathological parameters. We identified a distinct protein cluster enriched for AJ components that significantly correlated with response to FLOT chemotherapy. Among FLOT major responders, 94% exhibited high AJ expression. Low AJ expression occurred across histological subtypes, with varying frequencies: 27% in tubular-intestinal, 40% in mixed-type, and 50% in diffuse carcinomas. Low AJ expression was significantly associated with a pro-inflammatory tumor microenvironment and extracellular matrix (ECM) remodeling. AJ protein expression represents a potential predictive parameter for FLOT chemotherapy response in EAC and defines distinct phenotypes. The association between reduced AJ expression and inflammatory features suggests these tumors may represent candidates for further investigation of targeted therapeutic approaches, though the role of immunotherapy in this context remains to be determined. Pre-treatment AJ assessment could guide therapy selection to avoid ineffective therapies.

A cancer diagnosis can impose a financial burden on patients and their families, defined as socio-economic impact (SEI) within a framework of the Organization of European Cancer Institutes (OECI). The Socio-Economic Consequences of Cancer (SEC) study assessed SEI in 25 European countries using the Canadian Financial Index of Toxicity (FIT) instrument, showing substantial variation and supporting the need for a validated Europe-specific instrument. We examined the FIT instrument's validity and reliability in a secondary analysis of the SEC study, exploring whether the SEI framework supported its validation. Factor analyses were performed on the largest subgroup sharing cancer type, language, and country. The aim was to test whether the Canadian model could be replicated or a SEI-based model fit better. Reliability and construct validity were analyzed, followed by configural invariance and Differential Item Functioning (DIF) analysis for cross-country comparability. We used data from Bulgaria, France, Germany, the Netherlands, Norway, and Spain. The original FIT-instrument failed to replicate in the Spanish sample, leading to an SEI-based model with better fit (CFI = 0.975, RMSEA (90% CI) = 0.104 (0-0.278), χ² = 18, p = .60). The instrument was reliable. Construct validity was partly confirmed. Configural invariance testing suggested that the SEI-based model's factor structure fits better in Europe, while DIF was identified, implying that direct score comparisons across countries should be done with care. In conclusion, the original FIT-instrument could not be fully validated in Europe whereas the SEI-framework improved score interpretation, supporting its use in developing a validated instrument tailored to the European context.

Data on cancer risk in offspring of men with testicular germ cell cancer (TC) remain limited. We assessed the risk of childhood and adolescent and young adult (AYA) cancer in offspring of men with TC. Men diagnosed with TC in the Danish Cancer Registry (1943-2017) were identified (TC probands). For each TC proband, 10 men matched on birth year, alive, and cancer-free at the proband's date of diagnosis were selected from the National Civil Registration System (non-TC probands). Offspring were identified in the Danish Birth Registry, with cancer diagnoses obtained from national registries. Cumulative incidences, hazard ratios (HRs), with 95% confidence intervals (CIs) were calculated for childhood cancer (0-14 years) and AYA cancer (15-39 years), including TC specifically versus other cancers. Offspring were included regardless of whether they were born before or after their father's diagnosis (for TC probands) or the corresponding index date (for non-TC probands). Childhood cancer rates were similar between sons of TC probands and non-TC probands (HR 1.0, 95% CI 0.6-1.7) and daughters (HR 1.1, 95% CI 0.6-1.9). For AYA cancer, rates in daughters were comparable, while sons of TC probands had an increased rate (HR 1.9, 95% CI 1.6-2.4). This increase was driven by TC (HR 3.6, 95% CI 2.7-4.8), with no significant difference in rates of other cancers. The rate of childhood cancer in offspring of men with TC is comparable to the rate of the general population, while the elevated AYA cancer rate in sons is attributable to a higher rate of TC.

Tumor Treating Fields (TTFields) are an approved cancer therapy for glioblastoma (GBM), pleural mesothelioma, and non-small cell lung cancer (NSCLC). A recent phase 3 trial of TTFields therapy concomitant with standard-of-care gemcitabine and nab-paclitaxel (Gem/NabP) as a first-line treatment for unresectable, locally advanced pancreatic adenocarcinoma demonstrated a significant increase in overall survival. The current study evaluated the effects of TTFields in preclinical pancreatic ductal adenocarcinoma (PDAC) models. The vast majority of PDAC patients harbor KRAS mutations, which are associated with a more aggressive disease phenotype and increased therapy resistance, driven in part by overexpression of the key transcription factor c-Myc. In the current study, TTFields application significantly suppressed c-Myc expression and induced immunogenic cell death (ICD)-characterized by increased calreticulin cell-surface exposure, extracellular ATP secretion, and elevated HMGB1 release-in pancreatic cancer models. These effects were further enhanced when TTFields were applied concomitantly with Gem/NabP. Causality between c-Myc modulation and immune readouts was not established. In vivo, TTFields application induced a systemic immune response, evidenced by dendritic cell activation, increased effector memory T cells, and greater tumor leukocyte infiltration. TTFields concomitant with Gem/NabP significantly reduced tumor volume, decreased tumor monocytic myeloid-derived suppressor cells (M-MDSC), and increased the tumor lymphocyte-to-monocyte ratio (LMR) compared to all other treatment groups. These findings support the potential of TTFields to enhance therapeutic efficacy. Moreover, TTFields-induced tumor immunogenicity may enable combination strategies with immunotherapies. A phase 2 clinical trial investigating TTFields with Gem/NabP and immune checkpoint inhibitors (ICIs) for metastatic PDAC is currently underway.

Epithelial ovarian cancer (EOC) is a highly aggressive malignancy with poor prognosis. Thus, new treatment options are needed. Recently, lipid metabolism in EOC has been highlighted. However, the specific lipid molecules activating lipid metabolism remain unclear. This study aimed to elucidate lipid metabolism in EOC and evaluate the potential of its inhibition as a therapeutic approach. We obtained high-fat diet (HFD)-fed mouse serum and performed metabolome analysis to identify lipid molecules contributing to cell proliferation of EOC. We also analyzed which signaling pathway was activated by the lipid molecule. Finally, we demonstrated the inhibition of lipid metabolism in EOC cells. HFD significantly promoted tumor growth of EOC cells in vivo, and HFD-fed mouse serum promoted EOC cell proliferation in vitro. Metabolome analysis identified cholesterol (C₂₇H₄₆O) as a key molecule in HFD-fed mouse serum. Cholesterol (C₂₇H₄₆O) activated the Akt/mTOR signaling pathway in vitro. Cholesterol (C₂₇H₄₆O) is an important component of lipid rafts, and its inhibitor, which extracts cholesterol (C₂₇H₄₆O) from lipid rafts, inactivated the Akt/mTOR signaling pathway and suppressed subsequent EOC cell proliferation. Exogenous cholesterol (C₂₇H₄₆O) contributed to cell proliferation of EOC via the lipid rafts-Akt/mTOR signaling pathway, and its inhibition undoubtedly presents a novel therapeutic strategy for EOC.

Discoidin domain receptors (DDRs) are nonintegrin collagen receptors which could be activated by various collagens. Overexpressed in numerous cancers, DDRs participate in tumorigenesis, tumor growth, dissemination, and metastasis. Immune checkpoint inhibitors (ICIs) have demonstrated low response rates in tumors such as head and neck cancer and pancreatic cancer, possibly due to the insufficient presence of effector T cells and the abundant collagen fibers in the tumor microenvironment. Recently, several studies indicate that DDRs account for ICIs resistance. For instance, DDR1 can prevent the anti-tumor immune responses via mediating the rearrangement of collagen fibers, increasing the secretion of interleukin-18 (IL-18) as well as facilitating the formation of neutrophil extracellular traps (NETs). DDR2 may participate in the establishment of immunosuppressive tumor microenvironment by recruiting myeloid-derived suppressor cells (MDSCs) and promoting the M2 polarization of macrophages. Notably, the interaction between collagens and immune cells also acts as a pivotal role in mediating tumor immune escape. Targeting DDRs and upstream regulators including collagen has been reported to significantly restore the antitumor immunity or inhibit tumor development, such as utilizing DDR1 inhibitors via AI screening from FDA-approved therapeutics or natural products, and strategies for collagen synthesis inhibition or collagen degradation. However, the above approaches are largely limited to preclinical studies and still warrant further validation in clinical trials. Based on the current evidences, DDRs serve as promising targets for improving the efficacy of ICIs against cancers; more studies are anticipated to reveal unclarified mechanisms of DDRs in regulating anti-tumor immunity.

Prostate cancer (PC) screening reduces PC mortality but also causes burden such as overdiagnosis and unnecessary biopsies. The European Association of Urology (EAU) recently proposed a risk-adapted screening protocol incorporating prostate-specific antigen (PSA)-based intervals, a risk calculator (RC), and magnetic resonance imaging (MRI), though its long-term outcomes remain unquantified. We constructed the MIcrosimulation SCreening Analysis-PSA model by adapting the existing MIcrosimulation SCreening Analysis-PROstate microsimulation framework to simulate individual PSA trajectories. The model parameters were calibrated to outcomes of the European Randomized Study of Screening for Prostate Cancer (ERSPC). Using this model, we simulated five screening protocols for men aged 55-69: fixed 4-year intervals between PSA tests and a biopsy when PSA ≥3.0 ng/mL (ERSPC protocol); PSA-based intervals; MRI prior to biopsy; the RC and MRI prior to biopsy; and the full EAU protocol (PSA-based intervals, RC, and MRI). Outcomes included PC mortality, overdiagnoses, the number of PSA tests, biopsies, and MRIs. Compared to the ERSPC protocol, PSA-based intervals reduced PSA tests by 21%. The MRI-only protocol decreased overdiagnosis by 6% but also required many MRIs. Incorporating the RC further reduced overdiagnosis to 10% and required 36% fewer MRIs than the MRI-only protocol. The EAU combines the best of all these approaches while maintaining equal PC mortality (200 deaths per 10,000 men). The EAU protocol optimizes long-term screening efficiency, significantly reducing biopsies and overdiagnosis with minimal mortality trade-offs. MRI and RC integration enhance resource allocation.