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Background/Objectives: Outcome prediction in patients with estrogen (ER)-positive metastatic breast cancer (MBC) remains challenging. We investigated whether circulating tumor cell (CTC) count adds prognostic value in ER-positive MBC using immunohistochemical (IHC) or 16α-[18F]-fluoro-17β-estradiol (FES)-PET imaging. Methods: Patients with newly diagnosed non-rapidly progressive MBC receiving first-line endocrine monotherapy, with ER-positive IHC (biopsy) or FES-PET and available CTC count, were included. Associations of CTC count and CTC-ER status based on ESR1 mRNA expression with progression-free survival (PFS) and overall survival (OS) were analyzed, and the added prognostic value of CTC count (<5 vs. ≥5/7.5 mL) beyond a positive ER result was assessed. Results: In patients with ER-positive IHC (n = 98) or FES-PET (n = 99) out of 106 endocrine-treated patients, ≥5 CTCs were associated with shorter PFS (HR 1.86; p = 0.0047 and 1.75; p = 0.011) and OS (HR 3.19 and 3.22; both p < 0.01), respectively, compared with <5 CTCs. Adding CTC count to ER-positive IHC or FES-PET improved prognostic accuracy for PFS (p = 0.006 and 0.012) and OS (both p < 0.001). CTC-ER status (ESR1 RNA) was not associated with outcomes. Conclusions: CTC count adds prognostic value to PET- or biopsy-based ER analysis in endocrine-treated MBC.

Oncogene-induced replication stress characterizes many aggressive cancers. Several treatments are being developed that target replication stress, however, identification of tumors with high levels of replication stress remains challenging. We describe a gene expression signature of oncogene-induced replication stress. A panel of triple-negative breast cancer (TNBC) and non-transformed cell lines were engineered to overexpress CDC25A , CCNE1 or MYC , which resulted in slower replication kinetics. RNA sequencing analysis revealed a set of 52 commonly upregulated genes. In parallel, mRNA expression analysis of patient-derived tumor samples (TCGA, n  = 10,592) also revealed differential gene expression in tumors with amplification of oncogenes that trigger replication stress ( CDC25A , CCNE1 , MYC , CCND1 , MYB , MOS , KRAS , ERBB2 , and E2F1 ). Upon integration, we identified a six-gene signature of oncogene-induced replication stress ( NAT10 , DDX27 , ZNF48 , C8ORF33 , MOCS3 , and MPP6) . Immunohistochemical analysis of NAT10 in breast cancer samples (n = 330) showed strong correlation with expression of phospho-RPA ( R  = 0.451, p  = 1.82 × 10 −20 ) and γH2AX ( R  = 0.304, p  = 2.95 × 10 −9 ). Finally, we applied our oncogene-induced replication stress signature to patient samples from TCGA ( n  = 8,862) and GEO ( n  = 13,912) to define the levels of replication stress across 27 tumor subtypes, identifying diffuse large B cell lymphoma, ovarian cancer, TNBC and colorectal carcinoma as cancer subtypes with high levels of oncogene-induced replication stress.

PurposeCorrect identification of tumour receptor status is important for treatment decisions in breast cancer. [18F]FES PET and [18F]FDHT PET allow non-invasive assessment of the oestrogen (ER) and androgen receptor (AR) status of individual lesions within a patient. Despite standardised analysis techniques, interobserver variability can significantly affect the interpretation of PET results and thus clinical applicability. The purpose of this study was to determine visual and quantitative interobserver variability of [18F]FES PET and [18F]FDHT PET interpretation in patients with metastatic breast cancer.MethodsIn this prospective, two-centre study, patients with ER-positive metastatic breast cancer underwent both [18F]FES and [18F]FDHT PET/CT. In total, 120 lesions were identified in 10 patients with either conventional imaging (bone scan or lesions > 1 cm on high-resolution CT, n = 69) or only with [18F]FES and [18F]FDHT PET (n = 51). All lesions were scored visually and quantitatively by two independent observers. A visually PET-positive lesion was defined as uptake above background. For quantification, we used standardised uptake values (SUV): SUVmax, SUVpeak and SUVmean.ResultsVisual analysis showed an absolute positive and negative interobserver agreement for [18F]FES PET of 84% and 83%, respectively (kappa = 0.67, 95% CI 0.48–0.87), and 49% and 74% for [18F]FDHT PET, respectively (kappa = 0.23, 95% CI − 0.04–0.49). Intraclass correlation coefficients (ICC) for quantification of SUVmax, SUVpeak and SUVmean were 0.98 (95% CI 0.96–0.98), 0.97 (95% CI 0.96–0.98) and 0.89 (95% CI 0.83–0.92) for [18F]FES, and 0.78 (95% CI 0.66–0.85), 0.76 (95% CI 0.63–0.84) and 0.75 (95% CI 0.62–0.84) for [18F]FDHT, respectively.ConclusionVisual and quantitative evaluation of [18F]FES PET showed high interobserver agreement. These results support the use of [18F]FES PET in clinical practice. In contrast, visual agreement for [18F]FDHT PET was relatively low due to low tumour-background ratios, but quantitative agreement was good. This underscores the relevance of quantitative analysis of [18F]FDHT PET in breast cancer.Trial registrationClinicalTrials.gov, NCT01988324. Registered 20 November 2013, https://clinicaltrials.gov/ct2/show/NCT01988324?term=FDHT+PET&draw=1&rank=2.

Inadequate surgical margins occur frequently in oral squamous cell carcinoma surgery. Fluorescence molecular imaging (FMI) has been explored for intraoperative margin assessment, but data are limited to phase-I studies. In this single-arm phase-II study (NCT03134846), our primary endpoints were to determine the sensitivity, specificity and positive predictive value of cetuximab-800CW for tumor-positive margins detection. Secondary endpoints were safety, close margin detection rate and intrinsic cetuximab-800CW fluorescence. In 65 patients with 66 tumors, cetuximab-800CW was well-tolerated. Fluorescent spots identified in the surgical margin with signal-to-background ratios (SBR) of ≥2 identify tumor-positive margins with 100% sensitivity, 85.9% specificity, 58.3% positive predictive value, and 100% negative predictive value. An SBR of ≥1.5 identifies close margins with 70.3% sensitivity, 76.1% specificity, 60.5% positive predictive value, and 83.1% negative predictive value. Performing frozen section analysis aimed at the fluorescent spots with an SBR of ≥1.5 enables safe, intraoperative adjustment of surgical margins. By using tumor-specific fluorescent tracers, fluorescence molecular imaging (FMI) can be used to visualize tumor tissues with high specificity. Here the authors report the results of a phase II trial to evaluate the diagnostic accuracy of an EGFR-targeted FMI for intraoperative margin assessment in patients with oral squamous cell carcinoma.

During the last decade, the emerging field of molecular fluorescence imaging has led to the development of tumor-specific fluorescent tracers and an increase in early-phase clinical trials without having consensus on a standard methodology for evaluating an optical tracer. By combining multiple complementary state-of-the-art clinical optical imaging techniques, we propose a novel analytical framework for the clinical translation and evaluation of tumor-targeted fluorescent tracers for molecular fluorescence imaging which can be used for a range of tumor types and with different optical tracers. Here we report the implementation of this analytical framework and demonstrate the tumor-specific targeting of escalating doses of the near-infrared fluorescent tracer bevacizumab-800CW on a macroscopic and microscopic level. We subsequently demonstrate an 88% increase in the intraoperative detection rate of tumor-involved margins in primary breast cancer patients, indicating the clinical feasibility and support of future studies to evaluate the definitive clinical impact of fluorescence-guided surgery. Fluorescent tracers are being tested in clinical trials to improve detection of tumor margins, but procedures are not standardised. Here, the authors develop an analytical framework that is compatible with the workflow in the operating theatre, and show that it leads to an 88% increase in intraoperative detection of tumor margins in patients with breast cancer.

Background Metabolism-related metrics have been widely investigated for their relationship with breast cancer risk but are mostly based on single values. Weight gain during adulthood has been related to an increased risk of breast cancer, while the relationship with changes in glucose and lipids remain largely unknown. Methods Women aged 20–80 were included from the general population-based Lifelines cohort when they had two assessments: 2007–2013 and 2014–2017. The following metrics were measured once at each of the two periods: body mass index (BMI), waist to height ratio (WHtR), hemoglobin A1c (HbA1c), HDL cholesterol (HDL-C), total cholesterol (TC), and triglyceride (TG). Women with a history of cancer, follow up less than 12 months, or who were pregnant during assessments were excluded. Mean annual changes (mean ACs) were calculated for each metric between the two periods, and further categorized into three groups - decrease, no change, and increase. Cox proportional hazards models were conducted to estimate their associations with breast cancer occurrence, reporting adjusted hazard ratios (aHR) with 95% confidence intervals (CI). Results During a median of 92.3 months follow-up, 1,202 of 58,785 women were diagnosed with breast cancer. Among women with a baseline BMI < 25 kg/m 2 , a negative association between BMI decrease and breast cancer risk was observed in contrast to their counterparts with no change (aHR: 0.75, 95% CI: 0.56–0.99). In addition, relative to the no change group, breast cancer risk was positively associated with reductions in HbA1c (aHR: 1.23, 95% CI: 1.07–1.40) and TG (aHR: 1.26, 95% CI: 1.06–1.49). Conclusions Changes over time in this real-world dataset from the general population highlight the benefits of weight loss and the harms of decreased glucose and TG in relation to breast cancer risk. These longitudinal patterns are affected by age, BMI, and initial values, emphasizing the importance of personalized metabolic health management.

BackgroundThe development of IBD is known to involve early immunological alterations, but our understanding of the changes in antibody epitope repertoires moving from the prediagnostic phase towards disease onset remains incomplete.ObjectiveIn this study, we comprehensively characterised systemic antibody responses in patients with IBD before and after disease onset, aiming to identify prediagnostic disease biomarkers.DesignWithin Lifelines, a population-based cohort study collecting and storing longitudinal samples from 167 000 individuals over∼15 years, we identified 178 individuals with blood samples taken both before and after IBD-onset. In these prediagnosis and postdiagnosis serum samples (median time span 3.9 years), we profiled antibody epitope repertoires against 344 000 rationally selected microbial, food and immune antigens using phage-display immunoprecipitation sequencing.ResultsPostdiagnosis, we observe reduced antibody frequencies against herpesviruses, particularly for Epstein-Barr virus and varicella zoster virus, and elevated antibody frequencies against specific enteroviruses, including adenovirus C and enterovirus types B and C. Even before diagnosis, individuals who ultimately developed Crohn’s disease (CD) displayed elevated antibody reactivity against flagellins of both commensal and pathogenic bacteria. This CD-specific profile became even more pronounced postdiagnosis, suggesting the formation of IBD-specific antibody responses years before disease onset.ConclusionThis study is the first comprehensive high-resolution analysis of the exact antigenic nature of systemic antibody responses during the transition from prediagnostic to established IBD. The antibody signatures we found may represent a route to developing biomarkers that identify individuals at high risk of developing disease.

Complete tumor removal is crucial for successful surgical oncological outcomes. Targeted fluorescence imaging facilitates differentiation between healthy and cancerous tissue, enabling intraoperative margin assessment. However, its depth specificity is still limited. Three-dimensional fluorescence imaging could improve margin assessment, especially after tissue clearing. Conventional tissue clearing may take up to 24 h, limiting clinical applicability. This study developed and validated a fast tissue clearing protocol, achieving transparency within one hour. Ten patients from a fluorescence-guided surgery trial were included, from whom three tumor and three healthy tissue biopsies were acquired. These biopsies were used as control, cleared using a standard Benzyl Alcohol Benzyl Benzoate (BABB) clearing protocol, or cleared using the newly developed fast BABB clearing protocol. This protocol uses an orbital shaker, decreasing total process time to one hour. No significant difference in transparency was observed between normal and fast cleared biopsies. Fluorescence signals of all cleared biopsies increased directly after clearing and slowly decreased back to pre-cleared fluorescence signals over time. In non-cleared tumor biopsies, fluorescence intensity decreased substantially upon fixation, yet remained stable. Finally, clearing did not impact immunohistochemical staining. Therefore, fast tissue clearing is possible within one hour, enabling optical microscopy after tissue clearing for intraoperative pathology-assisted surgery.

Tissue glycation, assessed through skin autofluorescence (SAF) using an AGE reader, is linked to an increased risk of type 2 diabetes (T2D), cardiovascular disease (CVD), as well as mortality from both CVD and cancer. It was also suggested that higher SAF be linked to a greater incidence of cancer. We aimed to evaluate the relationship between SAF and the time to a new cancer diagnosis in the Lifelines Cohort Study, a population-based study in the Northern Netherlands, in participants with and without T2D. Initial participants’ screening was performed between 2006 and 2013. Detailed pathology diagnoses were obtained from the Dutch Nationwide Pathology Databank (Palga) and linked to Lifelines data up to March 2023. We performed Cox proportional hazards analyses adjusted for confounders to investigate the relationship between SAF and cancer incidence. A total of 77,961 participants (75,678 without T2D; 42% males; mean age 43 ± 12 years and 2,283 with T2D; 53% males; mean age 56 ± 12 years), who were free of cancer, were followed for a median of 11.5 years. Cumulative cancer incidence was 10.7% in males and 12.5% in females without diabetes, and 23.6% and 20.2% in males and females with T2D, respectively. SAF was significantly linked to an increased cancer incidence (HR 2.36, 95% CI 2.26–2.45, p  < 0.001) in the entire cohort. This relationship was significantly stronger in males than in females (HR 3.13, 95% CI 2.95–3.33, p  < 0.001 vs. 1.96, 95% CI 1.86–2.07, p  < 0.001). After adjusting for age, sex, waist circumference, body mass index, pack-years of smoking and presence of diabetes and metabolic syndrome, the association between SAF and cancer remained significant (HR 1.11, 95% CI 1.05–1.17, p  < 0.001). Sensitivity analyses for incident cancers diagnosed more than 2 years after baseline Lifelines screening and incident cancer after skin cancer exclusion yielded similar results. Especially lung, oesophageal and urinary tract cancer (all p  < 0.001) and ovarian, female genital and liver cancer ( p  < 0.05) were associated with increased SAF. Similarly, higher SAF was linked to increased cancer incidence in people with T2D (HR 1.76, 95% CI 1.50–2.06, p  < 0.001). This relationship was no longer statistically significant after adjusting for age and sex (HR 1.07, 95% CI 0.89–1.29) or for all confounders (HR 1.07, 95% CI 0.86–1.32). We conclude that, alongside its previously established application in evaluating the risk of future diabetes, CVD, as well as cause-specific mortality in people without diabetes, higher SAF measurements are linked to a slightly higher incidence of cancer.