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Sacituzumab govitecan (SG) is an antibody-drug conjugate approved for metastatic or unresectable locally advanced triple-negative breast cancer (mTNBC) after at least two prior systemic therapies, yet real-world evidence remains limited. We conducted a retrospective, multicenter study including 285 patients with unresectable locally advanced or metastatic TNBC treated with SG across 52 oncology centers in Turkey. Median progression-free and overall survival were 5.4 months (95% confidence interval [CI], 4.6-6.2) and 12.2 months (95% CI, 10.5-13.9), respectively, with a 12-month overall survival rate of 49.2%. The objective response rate and disease control rate in evaluable patients were 36.8% and 63.9%. Grades 3-4 adverse events, mainly neutropenia, occurred in 44.2% of patients. Dose reductions were needed in 20% of cases; no treatment-related deaths were reported. Our large real-world cohort reinforces the effectiveness and manageable safety profile of SG, mirroring pivotal trials, and highlights its value as a therapeutic option in diverse and heavily pretreated mTNBC populations.

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.

Modifiable risk factors, such as smoking, alcohol consumption, and excess weight, are associated with cancer incidence but data on their associations with population-based mortality among cancer patients are limited. Pooled data from seven health studies conducted in Finland during 1972-2015 were used to assess the associations of smoking, alcohol consumption, body mass index, physical inactivity, and education on mortality among 224,820 participants, of whom 10,637 were diagnosed with colorectal, lung, pancreatic, prostate or breast cancer. We estimated age-standardized relative survival and relative excess risks of death (RER) using piecewise constant excess hazard models. Current smoking was associated with increased excess mortality in male pancreatic cancer (RER compared with never-smokers 1.54, 95% CI 1.08-2.19) and prostate cancer patients (1.55, CI 1.08-2.23), as well as in female lung cancer patients (1.44, CI 1.07-1.92). Obesity was associated with increased excess mortality in prostate cancer patients (1.56, CI 1.06-2.30) and physical inactivity in colorectal cancer (1.33, CI 1.01-1.76 in men; 1.36, CI 1.06-1.74 in women) and male lung cancer patients (1.15, CI 1.02-1.30). Excess mortality was systematically elevated among patients with low education with statistically significant associations for male lung and female pancreatic cancer. Several lifestyle-related factors were associated with increased excess mortality among cancer patients but not consistently over all cancer sites or in both sexes. It is notable that even in a Nordic welfare state with potentially equal healthcare, marked socioeconomic inequalities persist in mortality among cancer patients.

Insulin resistance is an important risk factor for the development of colorectal cancer (CRC), and triglyceride-glucose (TyG) related indices, as emerging biomarkers of insulin resistance, have not been thoroughly studied in the context of CRC risk assessment. This study aimed to evaluate the relationships between three TyG-related indices-specifically triglyceride glucose-body mass index (TyG-BMI), triglyceride glucose-waist circumference index (TyG-WC), and triglyceride glucose-waist to height ratio index (TyG-WHtR)-and CRC risk within a large prospective cohort from the Kailuan Study (2006-2019), which included 173,342 cancer-free participants. During a median follow-up of 14.23 years, 977 incident CRC cases were identified. Multivariable Cox proportional hazards models revealed significant positive associations between the TyG-related indices and CRC risk: for TyG-BMI, those in the third and fourth quartiles had hazard ratios (HRs) of 1.22 (95% CI: 1.01-1.48) and 1.35 (95% CI: 1.11-1.64), respectively; for TyG-WC, the fourth quartile had an HR of 1.43 (95% CI: 1.17-1.74); and for TyG-WHtR, the third and fourth quartiles had HRs of 1.28 (95% CI: 1.05-1.57) and 1.37 (95% CI: 1.12-1.68), respectively. Dose-response analyses demonstrated linear relationships for all indices (all p for overall = 0.001, p for non-linear >0.05). The results show a significant association between elevated TyG indices and increased colorectal cancer (CRC) risk, suggesting that these markers may have potential value in risk stratification.

Progression from minimally invasive adenocarcinoma (MIA) to invasive adenocarcinoma (IA) in lung adenocarcinoma (LUAD) is associated with a significantly worse prognosis and lacks predictive markers. The genomic molecular mechanisms of progression and genetic signatures mediating the MIA to IA transition in early-stage LUAD are still largely uncharacterized. In our study, a genomic signature driving MIA to IA was developed by 243 MIA and 532 IA stage I LUAD patients, and its ability to predict outcomes was validated in multiple cohorts. Among patients with stage I LUAD, 19 genes exhibited significant differences in frequency between MIA and IA groups, with notable enrichment in the MAPK, PI3K-Akt and ErbB pathways. A genomic signature of 11 genes associated with LUAD invasion progression, with TP53 and CDKN2A playing key functional roles, was developed and correlated with poor prognosis by internal and external cohorts (p < 0.05). The high-risk group exhibited elevated tumor mutational burden, mutation-allele tumor heterogeneity, and variant allele frequency values both in train and validation cohorts (p < 0.001). Mixed ground-glass opacity and solid nodules, predominantly larger than 1 cm, were more common in the high-risk population (p < 0.001), while the low-risk group exhibited a higher proportion of high-medium differentiated LUAD (p < 0.001). Our results reveal an 11-gene genomic signature driving invasive progression from MIA to IA associated with poor outcome in stage I LUAD patients by validating internal and external cohorts, radiological, pathological and tumor size, with potential future implications for disease monitoring, prognosis, and future therapeutic interventions.

Despite demographic and socio-economic similarities between the Netherlands and Belgium, differences in survival for patients with esophageal and gastric cancer between the two countries exist. This population-based study investigated these survival differences with the aim of identifying explaining factors. We analyzed data from the Netherlands Cancer Registry (N = 26,980) and the Belgian Cancer Registry (N = 15,097) for patients diagnosed with esophageal or gastric cancer between 2010 and 2016. Survival differences were examined using relative survival, stratified for tumor location and stage. Factors that potentially mediated the survival differences were tested via multivariable excess hazard models controlling for baseline population mortalities. Five-year relative survival probability was significantly lower for patients from the Netherlands with esophageal cancer (EC) or gastric cancer (GC) (EC: 21% (20%-22%), GC: 20% (19%-21%)) compared to Belgian patients (EC: 24% (23%-25%), GC: 27% (25%-29%)). Across tumor stages, relative survival of patients with esophageal and gastric cancer was lower among patients from the Netherlands. Multivariable excess hazard modeling showed that survival differences of patients with stage IV disease disappeared when adjusting for treatment. This was not observed among patients with stage I-III gastric cancer, where survival differences remained after adjustment for treatment. Survival of patients with esophageal cancer and gastric cancer is generally higher in Belgium. For patients with stage IV disease, this difference can most likely be attributed to differences in treatment. Although treatment explains part of the survival differences for patients with curable disease, other causes remain largely unknown.

The association between mycotoxins and esophageal cancer (EC) risk remains poorly understood, highlighting the need for evidence from population-based prospective studies. We conducted a case-cohort study nested within the Taizhou Longitudinal Study to investigate this relationship, analyzing baseline urinary mycotoxins in 866 randomly selected subcohort members and 240 incident EC cases (including seven cases from the subcohort). Using ultra-high performance liquid chromatography-triple quadrupole-tandem mass spectrometry, we measured three mycotoxins: ochratoxin A (OTA), T-2 toxin (T-2), and fumonisin B1 (FB1). While FB1 was detectable in over 88% of urine samples, OTA and T-2 were detected in less than 30% of samples. EC cases showed slightly higher detection rates for all three mycotoxins compared to the subcohort subjects. Weighted Cox proportional hazards regression analyses for case-cohort studies revealed that, after adjusting for potential confounders, the urinary levels of three mycotoxins-OTA (hazard ratio [HR] = 1.07, 95% confidence interval [CI]: 0.73-1.56), T-2 (HR = 1.01, 95% CI: 0.51-2.00), and FB1 (HR = 0.94, 95% CI: 0.53-1.64)-as well as co-exposure to these three mycotoxins (HR = 1.33, 95% CI: 0.34-5.28), showed no significant association with EC risk. These results remained consistent even after excluding the first 2 years of follow-up to minimize the influence of potential reverse causation. Our case-cohort study found no clear associations between urinary mycotoxins-OTA, T-2, or FB1-and EC risk in the studied population.

Cervical screening frequency has not been studied in vaccinees. As the major risk factor, oncogenic human papillomavirus (HPV) is declining due to vaccination. We report a trial to assess the effectiveness of cervical screening frequency among women HPV-vaccinated as early adolescents (NCT02149030). In 2013, 5626 1992-1995-born women, who had received three doses of the HPV16/18 vaccine at ages 12-15 between 2007 and 2010 in a community-randomized vaccination trial (NCT00534638), were allocated at age 22 into high-intensity cytology-based cervical screening by even birth date (Arm A1) or into low-intensity cytology-based cervical screening by odd birth date (Arm A2). One thousand three hundred thirty-three women who received HPV16/18 vaccination at age 18 attended a safety of low intensity-screening arm (Arm A3). Low-intensity screening, where low-grade cytological abnormalities were not revealed for 6 years, was compared to the standard high-intensity screening used in Finland at the time. The prevalence of cytological and HPV findings was calculated at ages 22/25/28. The hazard ratio of histopathologically confirmed immediate cervical cancer precursors (HSIL/CIN2+) among participants was compared between low- and high-intensity screening arms. The overall occurrence of CIN2+ was comparable in Arms A1, 0.70% and A2, 0.66%, with the corresponding hazard ratio at age 28 being 0.97 (95% confidence intervals, 0.50-1.88). By age 28, the occurrence of vaccine-HPV types 16/18 was reduced up to 88% in the 12-to-15 compared to 18-year-old HPV-vaccinated women. In conclusion, the risk of CIN2+ was similar for HPV-vaccinated women who attended low-intensity cervical screening compared to high-intensity screening most likely due to the decline of oncogenic HPVs.

Phase 3 randomized controlled trials (RCTs) are key for assessing the efficacy and safety of new drugs used in hematologic malignancies. Up to 50% of patients with hematologic malignancies have renal impairment. The objective of this study was to perform a comprehensive analysis of the exclusion of patients with renal impairment from phase 3 RCTs of drugs administered systemically in leukemias, lymphomas, and multiple myeloma. Our analysis included 554 RCTs registered with ClinicalTrials.gov and started between 2009 and 2023. Overall, 370 (66.8%) RCTs had an exclusion criterion related to renal impairment. The most common criteria involved creatinine clearance/estimated glomerular filtration rate (GFR; n = 222; 40.1%) followed by serum creatinine level (n = 166; 30%). In multivariable analysis, the odds of the renal exclusion criteria were significantly higher in leukemia trials (adjusted odds ratio (OR), 1.62; 95% confidence interval (CI), 1.06-2.49; p = .03) and RCTs funded by commercial sponsors (adjusted OR, 1.66; 95% CI, 1.11-2.49; p = .01). Trials of chemotherapy were significantly associated with the odds of the renal exclusion criteria in univariate analysis (OR, 1.69; 95% CI, 1.18-2.41; p = .004), but not in multivariable analysis (adjusted OR 1.3; 95% CI 0.89-1.89; p = .18). While the nephrotoxic effects of anticancer drugs may occur more often in individuals with pre-existing renal decline, careful relaxation of the eligibility criteria in some trials should be considered to enable the investigators to assess the benefits and harms of the investigational drugs in the growing population of patients with a hematologic malignancy accompanied by renal impairment.

First-line chemo-immunotherapy has significantly improved survival in extensive-stage small-cell lung cancer (ES-SCLC). However, rapid disease progression still occurs, with a median progression-free survival (PFS) of only 4.5-5.8 months from induction therapy. We initiated two single-arm, phase II studies to assess the first-line maintenance therapy with tislelizumab plus anti-angiogenic drugs following induction therapy in ES-SCLC patients. Previously untreated ES-SCLC patients were enrolled to receive tislelizumab plus platinum-based chemotherapy as induction therapy for 4 cycles, followed by tislelizumab plus sitravatinib (Trial 1) or anlotinib (Trial 2) as maintenance therapy in a 21-day cycle. The primary endpoint was the 1-year PFS rate in the maintenance analysis set (MAS, including patients receiving ≥1 dose of maintenance therapy). Outcomes in MAS were calculated from the start of maintenance therapy. Twenty-one patients were enrolled, and 18 patients entered the maintenance phase in each trial. From the start of the maintenance therapy, the median PFS was 6.4 and 7.8 months (1-year PFS rates of 22.2% and not reached), respectively; the median overall survival (OS) was 18.3 months and not reached. From induction therapy, the corresponding median PFS was 9.1 and 10.8 months, with a median OS of 17.6 months and not reached. In MAS, the most common grade ≥3 treatment-related adverse events (TRAEs) included hypertension (22.2%) in Trial 1 and fatigue (5.6%) in Trial 2. No patients died from TRAEs in either trial. Maintenance therapy with tislelizumab plus sitravatinib or anlotinib yielded clinically meaningful survival results and was generally well tolerated in ES-SCLC, warranting further exploration in larger-scale trials.