Addition of tumor microenvironment immune cell composition to improve the performance of a predictive model for oral squamous cell carcinoma.

BACKGROUND: Conventional clinicopathological characteristics insufficiently predict prognosis in oral squamous cell carcinoma (OSCC). We aimed to assess the added predictive value of tumor microenvironment immune cell composition (TMICC) in addition to conventional clinicopathological characteristics. METHODS: Primary tumor samples of 290 OSCC patients were immunohistochemically stained for CD4, CD8, CD20, CD68, CD163, CD57, FoxP3 and Programmed cell Death Ligand 1. Additionally, clinicopathological characteristics were obtained from patients' medical files. Predictive models were trained and validated by conducting Least Absolute Shrinkage and Selection Operator (LASSO) regression analyses with cross-validation. To quantify the added predictive power of TMICC within models, receiver operating characteristic (ROC) analyses were used. RESULTS: Recurrence occurred in 74 patients (25.5%). Conventional clinicopathological characteristics (tumor localization, pathological T-stage, pathological N-stage, extracapsular spread, resection margin, differentiation grade, perineural invasion, lymphovascular invasion) and treatment modality, were used to build a LASSO logistic regression-based predictive model. Addition of TMICC to the model resulted in a comparable AUC of respectively 0.79 (±0.01) and 0.76 (±0.1) in the training and test sets. The model indicated that high numbers of CD4+ T cells protected against recurrence. Lymph node metastasis, extracapsular spread, perineural invasion, positive surgical margins and reception of adjuvant treatment were associated with increased risk for recurrence. CONCLUSIONS: The TMICC, specifically the number of CD4+ T cells, is an independent predictor , however, addition to conventional clinicopathological characteristics does not improve the performance of a predictive model for recurrence in OSCC.

Considerable interlaboratory variation in PD-L1 positivity for head and neck squamous cell carcinoma in the Netherlands- A nationwide evaluation study.

AIMS: Patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) are eligible for first-line immune checkpoint inhibition if their tumour is positive for programmed death ligand 1 (PD-L1) determined by the combined positive score (CPS). This nationwide study, using real-world data, investigated the developing PD-L1 testing landscape in the first 3 years after introduction of the test in HNSCC and examined interlaboratory variation in PD-L1 positivity rates. METHODS: Pathology reports of HNSCC patients mentioning PD-L1 were extracted from the Dutch Pathology Registry (Palga). Tumour and PD-L1 testing characteristics were analysed per year and interlaboratory variation in PD-L1 positivity rates was assessed using funnel plots with 95% confidence limits around the overall mean. RESULTS: A total of 817 PD-L1 tests were reported in 702 patients among 19 laboratories; 85.2% of the tests on histological material were stated to be positive. The national PD-L1 positivity rate differed significantly per year during the study period (79.7-89.9%). The use of the recommended 22C3 antibody increased from 59.9 to 74.3%. A total of 673 PD-L1 tests on histological material from 12 laboratories were analysed to investigate interlaboratory variation. Four (33%) deviated significantly from the national mean of PD-L1-positive cases using CPS ≥ 1 cut-off, while two (17%) deviated significantly for CPS ≥ 20 cut-off. CONCLUSION: In the first 3 years of PD-L1 assessment in HNSCC, the testing landscape became more uniform. However, interlaboratory variation in PD-L1 positivity rates between Dutch laboratories was substantial. This implies that there is a need for further test standardisation to reduce this variation.

Potential imaging targets in primary head and neck squamous cell carcinoma and lymph node metastases.

PURPOSE: To investigate glycoprotein nonmetastatic melanoma protein B (GPNMB) and vascular endothelial growth factor (VEGF) as potential fluorescent imaging markers by comparing their protein expression to epidermal growth factor receptor (EGFR). MATERIALS AND METHODS: Thirty-eight paired samples of untreated head and neck squamous cell carcinoma (HNSCC) primary tumours (PT) and corresponding synchronous lymph node metastases (LNM) were selected. After immunohistochemical staining, expression was assessed and compared by the percentage of positive tumour cells. Data were analysed using the Mann-Whitney test, effect sizes (ESr) and Spearman's correlation coefficient (r). RESULTS: GPNMB expression was observed in 100 % of PT, and median 80 % (range 5-100 %) of tumour cells, VEGF in 92 % and 60 % (0-100 %), EGFR in 87 % and 60 % (0-100 %) respectively. In corresponding LNM, GPNMB expression was observed in 100 % of LNM and median 90 % (20-100 %) of tumour cells, VEGF in 87 % and 65 % (0-100 %), and EGFR in 84 % and 35 % (0-100 %). A positive correlation was found between expression in PT and LNM for GPNMB (r = 0.548) and EGFR (r = 0.618) (p < 0.001), but not for VEGF (r = -0.020; p = 0.905). GPNMB expression was present in a higher percentage of tumour cells compared to EGFR in PT (p = 0.015, ESr = -0.320) and in LNM (p < 0.001, ESr = -0.478), while VEGF was not (p = 1.00, ESr = -0.109 and - 0.152, respectively). CONCLUSION: GPNMB expression is higher than EGFR in untreated HNSCC PT and corresponding LNM, while VEGF expression is comparable to EGFR. GPNMB is a promising target for fluorescent imaging in HNSCC.

RAD52-dependent mitotic DNA synthesis is required for genome stability in Cyclin E1-overexpressing cells.

Overexpression of Cyclin E1 perturbs DNA replication, resulting in DNA lesions and genomic instability. Consequently, Cyclin E1-overexpressing cancer cells increasingly rely on DNA repair, including RAD52-mediated break-induced replication during interphase. We show that not all DNA lesions induced by Cyclin E1 overexpression are resolved during interphase. While DNA lesions upon Cyclin E1 overexpression are induced in S phase, a significant fraction of these lesions is transmitted into mitosis. Cyclin E1 overexpression triggers mitotic DNA synthesis (MiDAS) in a RAD52-dependent fashion. Chemical or genetic inactivation of MiDAS enhances mitotic aberrations and persistent DNA damage. Mitosis-specific degradation of RAD52 prevents Cyclin E1-induced MiDAS and reduces the viability of Cyclin E1-overexpressing cells, underscoring the relevance of RAD52 during mitosis to maintain genomic integrity. Finally, analysis of breast cancer samples reveals a positive correlation between Cyclin E1 amplification and RAD52 expression. These findings demonstrate the importance of suppressing mitotic defects in Cyclin E1-overexpressing cells through RAD52.

Histopathological comparison of Sjögren-related features between paired labial and parotid salivary gland biopsies of sicca patients.

OBJECTIVES: To compare focus score (FS) and other histopathological features between paired labial and parotid salivary gland biopsies in a diagnostic cohort of suspected Sjögren's disease (SjD) patients. METHODS: Labial and parotid salivary gland biopsies were simultaneously obtained from patients with sicca complaints, suspected of having SjD. Biopsies were formalin fixed and paraffin embedded. Sections were stained with haematoxylin & eosin (H&E) and for CD3, CD20, CD45, cytokeratin, CD21, Bcl6, activation induced deaminase (AID), and IgA/IgG. FS and other histopathological features characteristic for SjD were analysed. RESULTS: Based on the expert opinion of three experienced rheumatologists, 36 patients were diagnosed as SjD and 63 as non-SjD sicca patients. When taking all patients together, absolute agreement of various histopathological features between labial and parotid biopsies was high and varied between 80% (FS) and 93% ((pre-)lymphoepithelial lesions (LELs)). More labial gland biopsies had a FS ≥ 1 compared with their parotid counterpart. Accordingly, the area of infiltrate was larger in labial gland biopsies. When considering only SjD patients, labial glands contained significantly less B-lymphocytes, GCs/mm2 and less severe LELs compared with parotid glands. CONCLUSION: Labial and parotid glands from SjD patients contain similar histopathological key features, and thus both glands can be used for diagnosis and classification of SjD. However, parotid salivary glands reveal more evident B-lymphocyte related features, while labial glands exhibit more inflammation, which may be partially unrelated to SjD.

Identification of new head and neck squamous cell carcinoma molecular imaging targets.

OBJECTIVES: Intraoperative fluorescence imaging (FI) of head and neck squamous cell carcinoma (HNSCC) is performed to identify tumour-positive surgical margins, currently using epidermal growth factor receptor (EGFR) as imaging target. EGFR, not exclusively present in HNSCC, may result in non-specific tracer accumulation in normal tissues. We aimed to identify new potential HNSCC FI targets. MATERIALS AND METHODS: Publicly available transcriptomic data were collected, and a biostatistical method (Transcriptional Adaptation to Copy Number Alterations (TACNA)-profiling) was applied. TACNA-profiling captures downstream effects of CNAs on mRNA levels, which may translate to protein-level overexpression. Overexpressed genes were identified by comparing HNSCC versus healthy oral mucosa. Potential targets, selected based on overexpression and plasma membrane expression, were immunohistochemically stained. Expression was compared to EGFR on paired biopsies of HNSCC, adjacent macroscopically suspicious mucosa, and healthy mucosa. RESULTS: TACNA-profiling was applied on 111 healthy oral mucosa and 410 HNSCC samples, comparing expression levels of 19,635 genes. The newly identified targets were glucose transporter-1 (GLUT-1), placental cadherin (P-cadherin), monocarboxylate transporter-1 (MCT-1), and neural/glial antigen-2 (NG2), and were evaluated by IHC on samples of 31 patients. GLUT-1 was expressed in 100 % (median; range: 60-100 %) of tumour cells, P-cadherin in 100 % (50-100 %), EGFR in 70 % (0-100 %), MCT-1 in 30 % (0-100 %), and NG2 in 10 % (0-70 %). GLUT-1 and P-cadherin showed higher expression than EGFR (p < 0.001 and p = 0.015). CONCLUSIONS: The immunohistochemical confirmation of TACNA-profiling results showed significantly higher GLUT-1 and P-cadherin expression than EGFR, warranting further investigation as HNSCC FI targets.

Correlation between Histopathological Prognostic Tumor Characteristics and [18F]FDG Uptake in Corresponding Metastases in Newly Diagnosed Metastatic Breast Cancer.

BACKGROUND: In metastatic breast cancer (MBC), [18F]fluorodeoxyglucose positron emission tomography/computed tomography ([18F]FDG-PET/CT) can be used for staging. We evaluated the correlation between BC histopathological characteristics and [18F]FDG uptake in corresponding metastases. PATIENTS AND METHODS: Patients with non-rapidly progressive MBC of all subtypes prospectively underwent a baseline histological metastasis biopsy and [18F]FDG-PET. Biopsies were assessed for estrogen, progesterone, and human epidermal growth factor receptor 2 (ER, PR, HER2); Ki-67; and histological subtype. [18F]FDG uptake was expressed as maximum standardized uptake value (SUVmax) and results were expressed as geometric means. RESULTS: Of 200 patients, 188 had evaluable metastasis biopsies, and 182 of these contained tumor. HER2 positivity and Ki-67 ≥ 20% were correlated with higher [18F]FDG uptake (estimated geometric mean SUVmax 10.0 and 8.8, respectively; p = 0.0064 and p = 0.014). [18F]FDG uptake was lowest in ER-positive/HER2-negative BC and highest in HER2-positive BC (geometric mean SUVmax 6.8 and 10.0, respectively; p = 0.0058). Although [18F]FDG uptake was lower in invasive lobular carcinoma (n = 31) than invasive carcinoma NST (n = 146) (estimated geometric mean SUVmax 5.8 versus 7.8; p = 0.014), the metastasis detection rate was similar. CONCLUSIONS: [18F]FDG-PET is a powerful tool to detect metastases, including invasive lobular carcinoma. Although BC histopathological characteristics are related to [18F]FDG uptake, [18F]FDG-PET and biopsy remain complementary in MBC staging (NCT01957332).

Narrow band imaging reveals field cancerisation undetected by conventional white light: Optical diagnosis versus histopathology.

OBJECTIVE: To assess whether narrow band imaging (NBI) detects fields of cancerisation around suspicious lesions in the upper aerodigestive tract, which were undetected by white light imaging (WLI). METHODS: In 96 patients with laryngeal and pharyngeal lesions suspicious for malignancy, 206 biopsies were taken during laryngoscopy: 96 biopsies of suspicious lesions detected by both WLI and NBI (WLI+/NBI+), 60 biopsies adjacent mucosa only suspicious with NBI (WLI-/NBI+), and 46 biopsies of NBI and WLI unsuspicious mucosa (WLI-/NBI-) as negative controls. Optical diagnosis according to the Ni-classification was compared with histopathology. RESULTS: Signs of (pre)malignancy were found in 88% of WLI+/NBI+ biopsies, 32% of WLI-/NBI+ biopsies and 0% in WLI-/NBI- (p < .001). In 58% of the WLI-/NBI+ mucosa any form of dysplasia or carcinoma was detected. CONCLUSION: The use of additional NBI led to the detection of (pre)malignancy in 32% of the cases, that would have otherwise remained undetected with WLI alone. This highlights the potential of NBI as a valuable adjunct to WLI in the identification of suspicious lesions in the upper aerodigestive tract.

Oncological and functional outcomes in T3 and T4 laryngeal cancer patients: choice for larynx preservation or total laryngectomy based on expected laryngeal function.

OBJECTIVE: To determine oncological and functional outcomes in patients with T3 and T4 laryngeal carcinoma, in which choice of treatment was based on expected laryngeal function and not T classification. METHODS: Oncological outcomes (disease-specific survival and overall survival) as well as functional outcomes (larynx preservation and functional larynx preservation) were analysed. RESULTS: In 130 T3 and 59 T4 patients, there was no difference in disease-specific survival or overall survival rates after radiotherapy (RT) (107 patients), chemoradiotherapy (36 patients) and total laryngectomy (46 patients). The five-year disease-specific survival rates were 83 per cent after RT, 78 per cent after chemoradiotherapy and 69 per cent after total laryngectomy, whereas overall survival rates were 62, 54 and 60 per cent, respectively. Five-year larynx preservation and functional larynx preservation rates were comparable for RT (79 and 66 per cent, respectively) and chemoradiotherapy (86 and 62 per cent, respectively). CONCLUSION: There is no difference in oncological outcome after (chemo)radiotherapy or total laryngectomy in T3 and T4 laryngeal carcinoma patients whose choice of treatment was based on expected laryngeal function.

Nasopharyngeal carcinoma: nationwide trends in subtype-specific incidence and survival over 3 decades in a non-endemic area.

PURPOSE: To identify trends in incidence and survival of NPC, subdivided by EBV status and histopathological subtype, over a 30-year period in the Netherlands. METHODS: Anonymized data from the Netherlands Cancer Registry and the Dutch Nationwide Pathology Databank (PALGA) for the period 1989-2018 were linked to identify and classify NPC cases. RESULTS: Incidence of NPC remained stable, with an annual percentage change (APC) of - 0.2. (95% CI - 0.9; 0.5). EBV testing became routine only in the last decade, the incidence of EBV-positive tumors remained stable over this period (APC 1.2, 95% CI - 1.3; 3.8). An increase in EBV-negative tumors (APC: 7.1, 95% CI 2.5; 11.9) and a decrease in untested tumors were found (APC: - 10.7, 95% CI - 15.7; - 5.7). The incidence of non-keratinizing, differentiated tumors increased (APC: 3.8, (95% CI 2.2; 5.5) while the incidence of other histological subtypes remained stable. Overall survival was better in patients diagnosed after 1998 (hazard ratio 0.8, 95% CI 0.6; 0.9). EBV status, histology, stage, and age were independently associated with relative excess risk of dying, but period of diagnosis was not. CONCLUSION: Testing for EBV increased over time, and a stable incidence of EBV-positive NPC over the last 10 years. The rising incidence of non-keratinizing, differentiated NPC mirrors data from the US and suggests a shift in non-endemic regions.

cGAS-STING pathway expression correlates with genomic instability and immune cell infiltration in breast cancer.

Genomic instability, as caused by oncogene-induced replication stress, can lead to the activation of inflammatory signaling, involving the cGAS-STING and JAK-STAT pathways. Inflammatory signaling has been associated with pro-tumorigenic features, but also with favorable response to treatment, including to immune checkpoint inhibition. In this study, we aim to explore relations between inflammatory signaling, markers of replication stress, and immune cell infiltration in breast cancer. Expression levels of cGAS-STING signaling components (STING, phospho-TBK1, and phospho-STAT1), replication stress markers (γH2AX and pRPA), replication stress-related proto-oncogenes (Cyclin E1 and c-Myc) and immune cell markers (CD20, CD4, and CD57) are determined immunohistochemically on primary breast cancer samples (n = 380). RNA-sequencing data from TCGA (n = 1082) and METABRIC (n = 1904) are used to calculate cGAS-STING scores. pTBK1, pSTAT1 expression and cGAS-STING pathway scores are all increased in triple-negative breast cancers compared to other subtypes. Expression of γH2AX, pRPA, Cyclin E1, c-Myc, and immune cell infiltration positively correlate with p-STAT1 expression (P < 0.001). Additionally, we observe significant positive associations between expression of pTBK1 and γH2AX, pRPA, c-Myc, and number of CD4+ cells and CD20+ cells. Also, cGAS-STING scores are correlated with genomic instability metrics, such as homologous recombination deficiency (P < 0.001) and tumor mutational burden (P < 0.01). Moreover, data from the I-SPY2 clinical trial (n = 71) confirms that higher cGAS-STING scores are observed in breast cancer patients who responded to immunotherapy combined with chemotherapy. In conclusion, the cGAS-STING pathway is highly expressed in TNBCs and is correlated with genomic instability and immune cell infiltration.

Presence of crown-like structures in breast adipose tissue; differences between healthy controls, BRCA1/2 gene mutation carriers and breast cancer patients.

PURPOSE: Crown-like structures (CLS) in breast adipose tissue are associated with inflammation and a potential factor in breast cancer behaviour. Whether this effect varies between breast cancer subtypes and is influenced by BMI and BRCA mutation status is presently unknown. Therefore, we compared CLS presence between adipose tissue of healthy controls, BRCA1/2 gene mutation carriers and breast cancer patients, and assessed the relation of CLS with clinical outcome in breast cancer patients. METHODS: Immunohistochemical staining for CD68 was performed on breast adipose tissue sections of 48 healthy controls, 78 BRCA1/2 gene mutation carriers and 259 breast cancer patients. CLS presence and index (CLS/cm2) were correlated with BMI, BRCA status, tumour presence, intrinsic tumour subtype and tumour characteristics. Associations with clinical outcome were assessed. RESULTS: CLS were more often present in breast cancer patients compared to BRCA carriers and healthy controls. CLS presence was associated with the presence of breast cancer and high BMI. CLS were more often present in Luminal-B-like tumours compared to the other subtypes. No correlations between CLS and BRCA status or age was found. In TNBC, CLS were related to lymphovascular invasion. No association with survival was found. CONCLUSION: In conclusion, CLS were more frequently present in breast adipose tissue of breast cancer patients compared to BRCA1/2 gene mutation carriers and healthy controls. Furthermore, our study provides evidence of the association between obesity and presence of CLS. The prognostic significance and impact on clinical outcome of differences in CLS numbers should be further assessed in prospective studies.

Increased Diagnostic Accuracy of the Labial Gland Biopsy in Primary Sjögren Syndrome When Multiple Histopathological Features Are Included.

OBJECTIVE: The aim of this study was to evaluate the diagnostic accuracy of the labial salivary gland biopsy based on multiple histopathological features in patients with suspected primary Sjögren syndrome (pSS). METHODS: Patients from a diagnostic sicca cohort with clinically suspected pSS who underwent a labial gland biopsy were included. Patients were categorized as having pSS or non-Sjögren syndrome sicca (non-SS sicca) based on vignettes scored by an expert panel. Labial gland biopsies were analyzed for the presence of four histopathological features: focus score (FS) ≥1, prelymphoepithelial and lymphoepithelial lesions, immunoglobulin G plasma cell shift, and germinal centers. Sensitivity and specificity of histologic features were calculated, and the optimal cutoff value for the number of histopathological features needed to diagnose pSS was determined with receiver operating curve analysis. RESULTS: A total of 38 patients were categorized as having pSS and 65 as having non-SS sicca. In labial gland biopsies of patients with pSS, the prevalence of FS ≥1 was 82%, followed by 68% for pre-lymphoepithelial and lymphoepithelial lesions, 63% for plasma cell shift, and 24% for germinal centers. Although FS ≥1 showed the highest sensitivity for patients with pSS (82%), specificity was higher for the other three features (98%-100%). The presence of two or more (of four) histopathological features had almost comparable sensitivity to FS alone, but specificity increased with 12% to 100%. For fulfillment of American College of Rheumatology/EULAR criteria, specificity increased from 84% to 95% when an abnormal biopsy was defined by the presence of two or more histopathological features instead of FS ≥1 only. CONCLUSION: The diagnostic accuracy of the labial gland biopsy increases when other histopathological features besides FS are taken into account, by reducing the number of false-positive biopsies.

Impact of health-related behavioral factors on participation in a cervical cancer screening program: the lifelines population-based cohort.

BACKGROUND: Regular participation in cervical cancer screening is critical to reducing mortality. Although certain sociodemographic factors are known to be associated with one-time participation in screening, little is known about other factors that could be related to regular participation. Therefore, this study evaluated the association between health-related behavioral factors and regular participation in cervical cancer screening. METHODS: The Lifelines population-based cohort was linked to data for cervical cancer screening from the Dutch Nationwide Pathology Databank. We included women eligible for all four screening rounds between 2000 and 2019, classifying them as regular (4 attendances), irregular (1-3 attendances), and never participants. Multinomial logistic regression was performed to evaluate the association between behavioral factors and participation regularity, with adjustment made for sociodemographic factors. RESULTS: Of the 48,325 included women, 55.9%, 35.1%, and 9% were regular, irregular, and never screening participants. After adjustment for sociodemographic factors, the likelihood of irregular or never screening participation was increased by smoking, obesity, marginal or inadequate sleep duration, alcohol consumption and low physical activity, while it was decreased by hormonal contraception use. CONCLUSION: An association exists between unhealthy behavioral factors and never or irregular participation in cervical cancer screening.

Immunohistological profiling confirms salivary gland-like nature of the tubarial glands and suggests closest resemblance to the palatal salivary glands.

BACKGROUND AND PURPOSE: High label uptake in 68 Ga-PSMA-11 PET/CT recently identified a bilateral nasopharyngeal structure as a salivary gland (SG)-like additional 'area of interest', to be considered in conditions affecting SGs. These structures were termed 'tubarial glands'. We aimed to further characterize their histological and immunohistochemical position compared to established SGs. METHODS: Tubarial gland tissue was compared with parotid, submandibular, sublingual, palatal and labial SGs tissue using immunohistological techniques. RESULTS: Expression of acinar cell-associated aquaporin-5 (AQP5) was detected in tubarial glands, in an apical location associated in control, established SGs with polarized, secretory acinar cells. Keratin14 (KRT14) expression in cells peripheral to AQP5+ clusters also suggested presence of myoepithelial cells. α-amylase, prolactin-induced protein, proline rich protein Haelll subfamily 2, and Muc5B expression suggests mucous acinar cell presence, and presence of muco-serous acinar cells peripheral to putative mucous acinar cells. Expression of adrenergic receptor-ß1 by acinar-like cells of the tubarial gland suggests ability to transduce sympathetic neuronal signaling. In terms of ductal architecture, tubarial glands contained large excretory-like ducts (similar to all other SGs), and squamous ducts, comprised of intermingled KRT14+ and KRT7+ cells. These squamous ducts were also observed in palatal, sublingual and labial SGs. No striated or intercalated ducts were observed, similar to palatal SGs. CONCLUSION: Based on histological and immunohistochemical analyses, the tubarial glands resemble SGs. They most convincingly echo characteristics of the palatal SGs in terms of ductal cells, and both the palatal and labial SGs when considering acinar cells.

EGFR-targeted fluorescence molecular imaging for intraoperative margin assessment in oral cancer patients: a phase II trial.

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.

Fibrotic Marker Galectin-3 Identifies Males at Risk of Developing Cancer and Heart Failure.

Background: Cancer and heart failure (HF) are the leading causes of death in the Western world. Shared mechanisms such as fibrosis may underlie either disease entity, furthermore it is unknown whether this relationship is sex-specific. Objectives: We sought to investigate how fibrosis-related biomarker galectin-3 (gal-3) aids in identifying individuals at risk for new-onset cancer and HF, and how this differs between sexes. Methods: Gal-3 was measured at baseline and at 4-year follow-up in 5,786 patients of the PREVEND (Prevention of Renal and Vascular Endstage Disease) study. The total follow-up period was 11.5 years. An increase of ≥50% in gal-3 levels between measurements was considered relevant. We performed sex-stratified log-rank tests and Cox regression analyses overall and by sex to evaluate the association of gal-3 over time with both new-onset cancer and new-onset HF. Results: Of the 5,786 healthy participants (50% males), 399 (59% males) developed new-onset cancer, and 192 (65% males) developed new-onset HF. In males, an increase in gal-3 was significantly associated with new-onset cancer (both combined and certain cancer-specific subtypes), after adjusting for age, body mass index, hypertension, smoking status, estimated glomerular filtration rate, diabetes mellitus, triglycerides, coronary artery disease, and C-reactive protein (HR: 1.89; 95% CI: 1.32-2.71; P < 0.001). Similar analyses demonstrated an association with new-onset HF in males (HR: 1.77; 95% CI: 1.07-2.95; P = 0.028). In females, changes in gal-3 over time were neither associated with new-onset cancer nor new-onset HF. Conclusions: Gal-3, a marker of fibrosis, is associated with new-onset cancer and new-onset HF in males, but not in females.

The natural history of ductal carcinoma in situ (DCIS) in simulation models: A systematic review.

OBJECTIVE: Assumptions on the natural history of ductal carcinoma in situ (DCIS) are necessary to accurately model it and estimate overdiagnosis. To improve current estimates of overdiagnosis (0-91%), the purpose of this review was to identify and analyse assumptions made in modelling studies on the natural history of DCIS in women. METHODS: A systematic review of English full-text articles using PubMed, Embase, and Web of Science was conducted up to February 6, 2023. Eligibility and all assessments were done independently by two reviewers. Risk of bias and quality assessments were performed. Discrepancies were resolved by consensus. Reader agreement was quantified with Cohen's kappa. Data extraction was performed with three forms on study characteristics, model assessment, and tumour progression. RESULTS: Thirty models were distinguished. The most important assumptions regarding the natural history of DCIS were addition of non-progressive DCIS of 20-100%, classification of DCIS into three grades, where high grade DCIS had an increased chance of progression to invasive breast cancer (IBC), and regression possibilities of 1-4%, depending on age and grade. Other identified risk factors of progression of DCIS to IBC were younger age, birth cohort, larger tumour size, and individual risk. CONCLUSION: To accurately model the natural history of DCIS, aspects to consider are DCIS grades, non-progressive DCIS (9-80%), regression from DCIS to no cancer (below 10%), and use of well-established risk factors for progression probabilities (age). Improved knowledge on key factors to consider when studying DCIS can improve estimates of overdiagnosis and optimization of screening.

Association of Tumor Microenvironment with Biological and Chronological Age in Head and Neck Cancer.

There is often a mismatch between the chronological and biological age of head and neck squamous cell carcinoma (HNSCC) patients. Treatment is based on chronological age, while biological age seems to be a better prognosticator for treatment toleration. This study investigated whether tumor characteristics are associated with chronological and biological age. The relation with survival was also assessed. Prospectively collected data from 164 newly diagnosed HNSCC patients enrolled in the OncoLifeS database were analyzed. Biological age was assessed by a multidomain geriatric assessment. Several immunological markers were tested by immunohistochemistry on tissue microarray sections from the tumor. Disease-free survival (DFS), adjusted for chronological- and biological age, was assessed by univariable and bivariable analyses. In biologically old patients, a lower infiltration of CD163+ macrophages (p = 0.036) as well as CD4+ (p = 0.019) and CD8+ (p = 0.026) lymphocytes was found in the tumor microenvironment. Chronological older patients showed significantly lower PD-L1 combined positive scores (p = 0.030). Advanced tumor stage and perineural growth were related to a worse DFS. None of the immunological markers showed a significant association with DFS. Biological age might have a stronger influence on tumor microenvironment than chronological age. These findings should initiate clinical studies investigating the response to specific treatment regimens (e.g., immunotherapy) according to the biological age.