International Journal of Cancer最新文献

Survival differences in rare histological prostate cancer (PCa) subtypes relative to age-matched population-based controls are unknown. Within Surveillance, Epidemiology, and End Results database (2004-2020), newly diagnosed (2004-2015) PCa patients were identified. Relying on the Social Security Administration Life Tables (2004-2020) with 5 years of follow-up, age-matched population-based controls (Monte Carlo simulation) were simulated for each patient. Kaplan-Meier analyses addressed survival rates. Of 582,220 patients, 580,368 (99.68%) harbored acinar, 867 (0.15%) ductal, 534 (0.09%) neuroendocrine, 368 (0.07%) mucinous, and 83 (0.01%) signet ring cell carcinoma. The metastatic stage was most prevalent in neuroendocrine (62%). In the localized stage, the overall survival difference at 5 years of follow-up was greatest in neuroendocrine (22% vs. 72%), signet ring cell (78% vs. 84%), and ductal carcinoma (71% vs. 77%). In the locally advanced stage, overall survival difference was greatest in neuroendocrine (16% vs. 79%), signet ring cell (75% vs. 91%), ductal (78% vs. 84%), and mucinous carcinoma (84% vs. 90%). In the metastatic stage, the overall survival difference was greatest in neuroendocrine (3% vs. 81%), mucinous (26% vs. 84%), and acinar carcinoma (27% vs. 85%). Regardless of stage, neuroendocrine carcinoma patients exhibit the least favorable life expectancy compared with population-based controls. Conversely, all other rare histological PCa subtypes do not meaningfully affect life expectancy in localized or locally advanced stages, except for locally advanced signet ring cell adenocarcinoma.

Chest x-ray (CXR) is widely used for lung cancer screening in Japan. We evaluated the sensitivity and specificity of CXR in detecting early lung cancer and its histological types. We cross-referenced lung cancer municipality screening data with the regional cancer registry database. The results of individuals screened at least once from 2016 to 2018 were utilized to calculate CXR's sensitivity and specificity for lung cancer diagnosed within 1 year of screening (n = 161,251) by stage and its histological types. We stratified analyses based on sex, age, smoking status, first screening, and screening intervals. CXR's sensitivity and specificity for early-stage lung cancer were 73.6% (95% confidence interval [CI], 66.8-79.6) and 94.1% (95% CI, 94.0-94.2), respectively. No significant differences were found in sex or smoking status. The sensitivity for early-stage adenocarcinoma was 76.0% (95% CI, 68.3-82.7), which was higher than that for early-stage squamous cell carcinoma (70.4% [95% CI, 67.3-86.0]). However, no significant differences were observed (p = .532). No significant differences were found in sex or smoking status for early-stage adenocarcinoma or early-stage squamous cell carcinoma. Due to its moderate sensitivity and high specificity, CXR could be a useful tool for mass screening in the general population. However, because CXR failed to detect 26.4% of early-stage cases, practitioners should inform high-risk patients of other screening options.

Myeloid cell leukemia 1 (MCL-1) is a member of the B-cell lymphoma 2 protein family and has anti-apoptotic functions. Deregulation of MCL-1 has been reported in several cancers, including lung and breast cancer. In the present study, the association of MCL-1 expression with molecular features in colorectal cancer (CRC) has been highlighted. CRC samples from Caris Life Sciences (Phoenix, AZ) were analyzed using NextGen DNA sequencing, whole transcriptome sequencing, whole exome sequencing, and immunohistochemistry (IHC); and stratified based on MCL-1 expression as top quartile MCL-1^high (Q4) and bottom quartile MCL-1^low (Q1). Immune cell infiltration (CI) in the tumor microenvironment (TME) was measured using RNA deconvolution analysis (QuanTIseq). MCL-1^high tumors were associated with an increased rate of programmed death ligand 1 IHC, higher T cell-inflamed signature, interferon score, microsatellite instability-high and tumor mutational burden-high status. MCL-1^high was associated with higher mutation rates of BCOR, TP53, KMT2D, ASXL1, KDM6A, ATM, MSH6, SPEN, KRAS, STK11, GNAS, RNF43, and lower mutation rates of CDKN1B, NRAS, and APC, and copy number amplifications in several genes. MCL-1^high TME had higher CI of M1 and M2 macrophages, B cells, natural killer cells, neutrophils, and T-regulatory cells infiltration, and lower CI of myeloid dendritic cells. Higher MCL-1 expression is significantly associated with favorable clinical outcomes in CRC cohorts. Our data showed a strong correlation between MCL-1 and distinct immune biomarkers and TME CI in CRC. Our findings suggest MCL-1 is a potential modulator of antitumor immunity, TME, and biomarker in CRC.

Lenvatinib plus pembrolizumab significantly improved efficacy versus sunitinib in treatment of advanced renal cell carcinoma (aRCC) in the phase 3 CLEAR study. We report results of an exploratory post hoc analysis of tumor response data based on baseline metastatic characteristics of patients who received lenvatinib plus pembrolizumab versus sunitinib, at the final overall survival analysis time point of CLEAR (cutoff: July 31, 2022). Treatment-naïve adults with aRCC were randomized to: lenvatinib (20 mg PO QD in 21-day cycles) plus pembrolizumab (n = 355; 200 mg IV Q3W); lenvatinib plus everolimus (not reported here); or sunitinib (n = 357; 50 mg PO QD; 4 weeks on/2 weeks off). The most common (lenvatinib plus pembrolizumab; sunitinib, respectively) metastatic site was lung (71.0%; 63.9%), followed by lymph node (45.6%; 43.7%), bone (22.5%; 24.9%), and liver (17.7%; 19.6%). Across treatment arms, ≥65% had two or more metastatic organs/sites involved, >80% of patients had nontarget lesions, and ~45% had baseline sums of diameters of target lesions ≥60 mm. Lenvatinib plus pembrolizumab demonstrated greater progression-free survival, objective response rate, and duration of response versus sunitinib across evaluable subgroups regardless of site or size of baseline metastasis or number of metastatic sites at baseline. Overall survival generally trended to favor lenvatinib plus pembrolizumab versus sunitinib; and tumor shrinkage was greater across sites (lung, lymph node, liver, and bone) for patients in the lenvatinib-plus-pembrolizumab arm versus the sunitinib arm. These results further support lenvatinib plus pembrolizumab as a standard-of-care in patients with aRCC regardless of site or size of baseline metastasis or the number of metastatic sites.

Overcoming luminal breast cancer (BrCa) progression remains a critical challenge for improved overall patient survival. RUNX2 has emerged as a protein related to aggressiveness in triple-negative BrCa, however its role in luminal tumors remains elusive. We have previously shown that active FGFR2 (FGFR2-CA) contributes to increased tumor growth and that RUNX2 expression was high in hormone-independent mouse mammary carcinomas. To elucidate the interaction between FGFR2 and RUNX2 in human BrCa, we investigated their roles in tumor progression and treatment responsiveness. Increased FGFR2 activity resulted in higher RUNX2 expression, cell proliferation, and metastasis. In contrast, silencing FGFR2 reduced these parameters. Overexpression of RUNX2 in FGFR2-silenced cells rescued the inhibitory effects, promoting a more aggressive phenotype, even if compared with the wt RUNX2-transfected cells, which also had increased aggressiveness compared with naïve-transfected cells. RUNX2-overexpressing tumors were insensitive to endocrine- or FGFR inhibitor treatments. Notably, the CBFβ-RUNX complex inhibitor, AI-14-91, demonstrated great effectiveness in vitro. In a small cohort of luminal BrCa patients, nuclear RUNX2 expression was associated with tumor recurrence. Transcriptomic analysis strongly supported these data showing that patients with luminal carcinomas with high RUNX2 activity score have a worse progression-free interval than those with low RUNX2 activity. Our findings suggest a complex interplay between FGFR2 and RUNX2 in regulating tumor aggressiveness. This study underscores the significance of RUNX2 in luminal BrCa progression and posits RUNX2 as a promising therapeutic target and as a potential prognostic biomarker in luminal BrCa patients.

Sterile alpha motif and HD domain-containing protein 1 (SAMHD1) is a dNTP hydrolase important for intracellular dNTP homeostasis and serves as tumor suppressor and modulator of antimetabolite efficacy in cancer, though largely unexplored in breast cancer (BC). A cohort of patients with early BC (n = 564) with available gene expression data (GEP) was used. SAMHD1 protein expression was assessed by immunohistochemistry performed on tissue microarrays. A large pooled transcriptomic dataset was used for validation (n = 2402). GEP data from the metastatic TEX randomized phase III trial (NCT01433614) were used for SAMHD1 predictive evaluation in response to capecitabine. SAMHD1 protein and mRNA levels were higher in HER2-enriched/HER2+ and basal-like (BL)/ER-/HER2- BC. Both SAMHD1 gene and protein expression were independently associated with favorable outcomes in BL tumors. In the pooled dataset, SAMHD1 gene expression was independently associated with favorable disease-free survival in the entire population and within the BL and HER2-enriched molecular subtypes. In metastatic BC, SAMHD1 mRNA levels were higher in responders receiving capecitabine. In conclusion SAMHD1 gene and protein expression represent promising prognostic biomarkers in BL early BC.

Wilms tumor (WT) is the most common kidney cancer in infants and young children. The determination of the clonality of bilateral WTs is critical to the treatment, because lineage-independent and metastatic tumors may require different treatment strategies. Here we found synchronous bilateral WT (n = 24 tumors from 12 patients) responded differently to preoperative chemotherapy. Transcriptome, whole-exome and whole-genome analysis (n = 12 tumors from 6 patients) demonstrated that each side of bilateral WT was clonally independent in terms of somatic driver mutations, copy number variations and transcriptomic profile. Molecular timing analysis revealed distinct timing and patterns of chromosomal evolution and mutational processes between the two sides of WT. Mutations in WT1, CTNNB1 and copy-neutral loss of heterozygosity of 11p15.5 provide possible genetic predisposition for the early initiation of bilateral WT. Our results provide comprehensive evidence and new insights regarding the separate initiation and early embryonic development of bilateral WT, which may benefit clinical practices in treating metastatic or refractory bilateral WT.

Cancer is the second leading cause of death in Turkey, with nearly one in six deaths attributed to the disease. In 2018, Turkey recorded 211,273 new cancer cases. Many cancers are linked to modifiable lifestyle risk factors, such as tobacco use, alcohol consumption, obesity, and inadequate diet and physical activity. Modifying these risk factors could potentially prevent 30%-50% of cancer cases and deaths. This study aims to estimate the population attributable fraction (PAF) of cancer cases and deaths due to various modifiable risk factors in Turkey. Modifiable cancer risk factors were identified as smoking, infections, obesity, physical inactivity, alcohol consumption, inadequate intake of fruits, vegetables, fiber, and calcium. Data on exposure prevalence and cancer incidence were sourced from national surveys and reports. Relative risks (RRs) were obtained from global studies. PAFs were calculated using Levin's equation, accounting for overlaps between risk factors. In 2018, 32% of the cancer cases were attributable to lifestyle risk factors. Smoking was the most significant factor, accounting for 28.4% of cases in men, while high BMI was the leading factor in women, contributing to 11.5% of cases. Lifestyle risk factors were responsible for 41.6% of cancer deaths, with smoking being the leading cause. Lifestyle risk factors contribute significantly to cancer incidence and mortality in Turkey. Prioritizing interventions to reduce tobacco use and obesity could substantially lower the cancer burden. These results are crucial for developing effective cancer prevention strategies and informing public health policies.

The biology of cancer is characterized by an intricate interplay of cells originating not only from the tumor mass, but also its surrounding environment. Different microbial species have been suggested to be enriched in tumors and the impacts of these on tumor phenotypes is subject to intensive investigation. For these efforts, model systems that accurately reflect human-microbe interactions are rapidly gaining importance. Here we present a guide for selecting a suitable in vitro co-culture platform used to model different cancer-microbiome interactions. Our discussion spans a variety of in vitro models, including 2D cultures, tumor spheroids, organoids, and organ-on-a-chip platforms, where we delineate their respective advantages, limitations, and applicability in cancer microbiome research. Particular focus is placed on methodologies that facilitate the exposure of cancer cells to microbes, such as organoid microinjections and co-culture on microfluidic devices. We highlight studies offering critical insights into possible cancer-microbe interactions and underscore the importance of in vitro models in those discoveries. We anticipate the integration of more complex microbial communities and the inclusion of immune cells into co-culture systems to more accurately simulate the tumor microenvironment. The advent of ever more sophisticated co-culture models will aid in unraveling the mechanisms of cancer-microbiome interplay and contribute to exploiting their potential in novel diagnostic and therapeutic strategies.