International Journal of Cancer最新文献

Pancreatic cancer (PCA) is the third leading cause of cancer-related death in Europe. Despite recent therapeutic advances, patients experience rapid health deterioration. Based on previous results, the Platform for Outcome, Quality of Life, and Translational Research on Pancreatic Cancer-PARAGON (NCT04119362) was initiated to investigate the whole life cycle of PCA patients. Between November 2019 and October 2021, 469/479 screened patients were enrolled in 46 sites. Demographic, clinical, and quality of life (QoL) data were collected. The treatment landscape was depicted using Sankey diagrams. Median overall survival (mOS) for all patients in first line was 10.6 months (95% confidence interval [CI], 9.2-11.7 months). With mFOLFIRINOX as first-line treatment, mOS was 11.3 months (95% CI, 8.6-13.5 months), with gemcitabine/nab-paclitaxel 10.5 months (95% CI, 8.3-12.9 months). The mean Global Health Status for patients that proceeded from first to second line did not substantially deteriorate during first line. Predictive variables for proceeding from first to second-line therapy were reasons for ending first-line treatment (patient's wish, toxicity, and progressive disease) and age. In summary, we were able to show in detail patient flows and QoL data throughout all therapy lines, which will help to further understand the major clinical checkpoints of the disease.

Most cutaneous malignant melanomas (CMMs) are thin (≤1.0 mm, stage T1) with an expected 10-year melanoma-specific survival of 93%-97%. The incidence of CMM is higher in groups with high socioeconomic status (SES). We aimed to assess overall survival (OS) and detailed characteristics in individuals with thin CMM as compared to the general population matched on age, sex, and county of residence. Matched cohort study comprising patients diagnosed between 2001 and 2018 with thin CMM (cases) and melanoma-free comparators from the general population. Patients and comparators were identified in the Malignant Melanoma Data Base Sweden. Multivariable Cox regression analyses were applied to compare the mortality risk for cases and comparators with adjustments for SES and comorbidities. We identified 25,843 cases and 127,383 comparators. Cases had higher SES and less comorbidity. No significant differences in OS were found. However, in the T1a subgroup, comprising 16,941 cases, the 5-year OS was significantly better than in comparators (n = 83,510) (92.5% (95% CI 92.1%-93.0%) versus 91.1% (95% CI 90.8%-91.3%), p <.001). The adjusted mortality risk was slightly higher for the whole T1 group (HR 1.05, 95% CI 1.01-1.09), while no difference was found for the T1a subgroup. Deaths attributed to cardiovascular disease, dementia, and chronic obstructive pulmonary disease were less common in CMM patients. Patients diagnosed with thin CMM have an OS similar to or even better than the general population since they are at a lower risk of death from other diseases, likely reflecting socioeconomic and lifestyle factors.

This study examined the associations of diabetes status, duration, and age at onset with lung cancer risk in the China Kadoorie Biobank. We prospectively assessed the association between diabetes status and lung cancer risk in 510,148 cancer-free participants, with analyses of duration and age at onset among 29,962 participants with diabetes at baseline. Multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox regression models, and effect modification was assessed across stratified subgroups using likelihood ratio tests. During a median 9.17-year follow-up, 5007 lung cancer cases occurred. Compared with participants without diabetes, those with diabetes had a higher lung cancer risk (HR = 1.15, 95% CI: 1.01-1.32). Diabetic patients with onset <40 years showed a 2.81-fold higher lung cancer risk (95% CI: 1.31-6.02) compared to ≥60-year onset groups. Longer duration (≥15 vs. <1 year) was associated with increased risk (HR = 2.06, 95% CI: 1.33-3.19). The association with diabetes status was stronger among individuals with below-median physical activity, while the association with diabetes duration was more pronounced in overweight participants. Overall, these findings indicate that diabetes, especially with earlier onset and longer duration, significantly increases lung cancer risk, highlighting the need for screening and targeted management in high-risk populations.

Benefits and harms of breast cancer (BC) screening with mammography have been debated and, although most studies reported positive effects, some studies found a negative effect in terms of net quality-adjusted life years (QALYs). We aimed to estimate net QALYs associated with biennial mammographic screening for women aged 50-69 years offered to 100,000 women followed until age 85, using various assumptions on BC mortality reduction, overdiagnosis and mortality transfer (the extent to which a reduction in BC mortality results in a reduction in all-cause mortality). Individual-level data from women invited to BreastScreen Norway during 1996-2020 were used to perform the calculations. The three baseline scenarios included (1) Model Microsimulation Screening Analysis (MISCAN): MISCAN prediction for mortality reduction and overdiagnosis proportion; (2) Model A: 40% BC mortality reduction and 15% overdiagnosis; and (3) Model B: 20% BC mortality reduction and 50% overdiagnosis. For all scenarios, an 80% mortality transfer was assumed. An online tool was developed to illustrate the impact of alternative assumptions. Biennial organized mammographic screening for women aged 50-69 years who were followed until the age of 85 years was associated with 6819, 7444 and 2446 net QALYs gained per 100,000 women for Model MISCAN, A and B, respectively. Assumptions on BC mortality reduction exhibited the largest impact on net QALYs. To conclude, even when assuming a high overdiagnosis proportion and low BC mortality reduction, net QALYs remained positive, reinforcing the value of offering BC screening with mammography to Norwegian women and showing its potential to improve health outcomes.

Exercise protects against colon cancer progression, but the underlying biological mechanisms remain unclear. One proposed mechanism is the release of bioactive molecules into the systemic circulation during exercise, which may act directly on tumour cells to suppress DNA damage, inhibit proliferation, and preserve genomic stability. Here, we profiled the serum proteomic response to acute exercise and evaluated the effects of exercise-conditioned human serum on DNA damage kinetics and transcriptomic signatures in colon cancer cells. Blood samples were collected from 30 overweight/obese adults before and immediately after a maximal incremental cycling test. LoVo cells were exposed to pre- or post-exercise serum, treated with 2 Gy irradiation, and assessed for γ-H2AX foci over 24 h. Acute exercise increased the relative abundance of 13 proteins in serum (p < 0.05), including interleukin-6 (IL-6) and its soluble receptor IL-6R, reflecting systemic activation of acute-phase immune and vascular signalling. Compared to pre-exercise serum, post-exercise serum significantly reduced γ-H2AX foci in LoVo cells at 6 h (p = 0.010) and decreased the area under the curve (p = 0.014), indicating accelerated DNA repair. Post-exercise serum also increased expression of the DNA repair gene PNKP, with and without irradiation (p = 0.007 and p = 0.029, respectively). Transcriptomic analysis revealed upregulation of mitochondrial energy metabolism and downregulation of cell cycle and proteasome-related pathways. These findings suggest that acute exercise elicits systemic responses that enhance DNA repair and shift colon cancer cells towards a less proliferative transcriptomic state under sublethal genotoxic stress, offering a potential mechanistic explanation for the protective effects of exercise against colorectal carcinogenesis.

Lynch syndrome is a germline cancer predisposition syndrome caused by a variant in one of four genes. Lynch syndrome places individuals at significantly higher risk for a range of cancers, especially colorectal and endometrial. Depending on which gene is affected, the risk of ovarian, gastric, small bowel, pancreatic, biliary urothelial, brain, and certain skin tumors is also increased. Tailored treatment, cancer surveillance, and consideration of primary prevention measures are critical for at-risk individuals. Despite advancements in genetic testing, Lynch syndrome remains underdiagnosed, with only a small proportion of those affected aware of their genetic predisposition. This article explores the patient experience of living with Lynch syndrome, focusing on the challenges surrounding diagnosis, risk-adjusted prevention, healthcare coordination, and information dissemination. Stages of the patient journey are explored, from awareness and suspicion to diagnosis, treatment and surveillance, psychosocial adaptation, and ongoing management. The need for more comprehensive healthcare strategies and better communication to enhance the quality of care for Lynch syndrome patients is emphasized. We recommend improvements to better meet patient needs.

The immunosuppressive tumor microenvironment, characterized by limited immune cell infiltration, represents a major challenge for effective immunotherapy in hepatocellular carcinoma (HCC). Epigenetic dysregulation has emerged as a critical mechanism underlying tumorigenesis and progression; however, the specific epigenetic mechanisms governing immune infiltration remain poorly understood. Here, we investigated the role of G9a, a histone methyltransferase catalyzing H3K9 methylation, in modulating anti-tumor immunity in HCC. Bioinformatic analysis of human HCC datasets revealed a significant inverse correlation between G9a expression and T cell infiltration. Genetic ablation of G9a in hepatoma cells markedly enhanced CD8⁺ T cell recruitment and activation in immunocompetent mouse models. Through RNA sequencing and functional validation, we identified CXCL10 as the key chemokine directly repressed by G9a. Mechanistically, G9a mediates H3K9 dimethylation at the CXCL10 promoter, and G9a deletion or inhibition significantly reduced this repressive mark, resulting in increased CXCL10 expression and secretion. Importantly, neutralization of CXCL10 abolished G9a inhibition-induced enhancement of CD8⁺ T cell migration. In preclinical models, pharmacological inhibition of G9a with UNC0642 not only suppressed tumor growth by promoting T cell infiltration but also synergized with anti-PD1 therapy to achieve superior therapeutic efficacy. These findings establish G9a as an epigenetic regulator of anti-tumor immunity in HCC and provide evidence for combining G9a inhibitors with immune checkpoint blockade to improve outcomes for HCC patients who are receiving immunotherapy.

High-grade serous ovarian carcinoma (HGSC) is the most lethal form of ovarian carcinoma, often diagnosed at advanced stages due to non-specific symptoms and the lack of reliable screening methods. This proof-of-concept study aimed to develop a robust TP53 mutation panel for detecting HGSC through targeted DNA sequencing in both liquid and solid biopsies. We constructed a custom TP53 gene panel and utilized a PCR-based unique molecular identifier approach for next-generation sequencing to analyze 94 samples from 11 patients diagnosed with HGSC, including primary tumor, plasma, ascites, ovarian cyst fluid, vaginal, endocervical and endometrial samples. Detected TP53 mutations were analyzed, categorized, and their frequencies calculated. Pathogenic TP53 mutations were identified in all patients, with 91% of the patients exhibiting one unique paired mutation across three or more sample types. The panel demonstrated high sensitivity and technical reproducibility, successfully detecting TP53 mutations across all sample types, with as little as 2.6 ng of DNA. TP53 mutations were consistently found in ascites, ovarian cyst fluid, and plasma samples, confirming the presence of pathogenic mutations in each sample type across all patients. This study underscores the potential of liquid biopsies in clinical molecular diagnostics. The TP53 mutation panel presented in this proof-of-concept study offers a promising approach for differential diagnostics and detection of HGSC, informative data prior to extended investigation and first-line treatment guidance.