Biomarker expression and impact on clinical outcomes in an international study of chemoradiation and MRI-based image-guided brachytherapy for locally advanced cervical cancer: BIOEMBRACE.

PURPOSE: BIOEMBRACE-I was designed to study the impact of biomarkers in addition to clinic-pathological factors on disease outcomes in patients treated with chemoradiation and MRI-guided brachytherapy (BT) for locally advanced cervical cancer in EMBRACE study. PATIENT AND METHODS: Between 2018-2021, eight EMBRACE-I sites contributed tumour tissue for immunohistochemistry of p16, PD-L1 and L1CAM. These biomarkers and clinicopathological factors (FIGO 2009 stage, nodal status, histology, necrosis on MRI) were analysed to predict poor response at brachytherapy (BT) (high-risk clinical target volume [HR-CTV] ≥40cc) at BT), and 5-year local control, pelvic control and disease-free survival (DFS). Interaction between p16, PD-L1, radiotherapy dose (HR-CTV D90) and disease outcomes was investigated. Univariable and multivariable analysis were performed. RESULTS: Two-hundred sixty-four patients were included. The median HR-CTV D90 was 89 (86-95) Gy. p16 positive (pos), PD-L1>1% and L1CAM ≥ 10% was noted in 86.6%, 20.1% and 17.8% respectively. P16 negative (neg) status (OR 2.0 (1.0-5.7), p=0.04), necrosis on MRI (OR 2.1 (1.1-4.3), p<0.02) independently predicted for HR-CTV≥40cc, as did FIGO stage and tumour width >5cm. PDL1>1% was associated with reduced local (82% vs. 94%, p=0.02) and pelvic control (79% vs. 89%, p=0.02). HR-CTV D90 <85Gy was associated with inferior 5-year local control in p16+ patients especially if PD-L1 was co-expressed. On multivariable analysis, PD-L1>1% was the only independent factor for 5-year local control (HR 3.3, p=0.04) and L1CAM ≥50% for pelvic control (HR 5.5 (1.3-23.3), p =0.02). CONCLUSIONS: P16 neg status and tumor necrosis on MRI are independently associated with poor response to chemoradiation, whereas PD-L1>1% and L1CAM≥50% have an independent impact on local and pelvic control suggesting impact of biomarker expression on outcomes. Further validation is needed.

Predictors of treatment response in lymphogenic metastasized papillary thyroid cancer: a histopathological study.

BACKGROUND: Lymph node metastases in papillary thyroid cancer (PTC) increase the risk for persistent and recurrent disease. Data on the predictive value of histopathological features of lymph node metastases, however, are inconsistent. The aim of this study was to evaluate the prognostic significance of known and new histopathological features of lymph node metastases in a well-defined cohort of PTC patients with clinically evident lymph node metastases. METHODS: A total of 1042 lymph node metastases, derived from 129 PTC patients, were reexamined according to a predefined protocol and evaluated for diameter, extranodal extension, cystic changes, necrosis, calcifications, and the proportion of the lymph node taken up by tumor cells. Predictors for a failure to achieve a complete biochemical and structural response to treatment were determined. RESULTS: The presence of more than 5 lymph node metastases was the only independent predictor for a failure to achieve a complete response to treatment (odds ratio [OR] 3.39 [95% CI, 1.57-7.33], P < .05). Diameter nor any of the other evaluated lymph node features were significantly associated with the response to treatment. CONCLUSIONS: Detailed reexamination of lymph nodes revealed that only the presence of more than 5 lymph node metastases was an independent predictor of failure to achieve a complete response to treatment. No predictive value was found for other histopathological features, including the diameter of the lymph node metastases. These findings have the potential to improve risk stratification in patients with PTC and clinically evident lymph node metastases.

Topical imiquimod treatment of residual or recurrent cervical intraepithelial neoplasia lesions (TOPIC-2): A randomised controlled trial.

OBJECTIVE: To investigate the efficacy of imiquimod in women with residual or recurrent cervical intraepithelial neoplasia (rrCIN), compared with large loop excision of the transformation zone (LLETZ). DESIGN: Randomised controlled non-inferiority trial. SETTING: One academic and one regional hospital in the Netherlands. POPULATION: Thirty-five women with rrCIN were included in the study between May 2016 and May 2021. METHODS: Women were randomised to receive treatment with 5% imiquimod cream (12.5 mg) intravaginally (three times a week for a duration of 16 weeks) or a LLETZ procedure (standard treatment). MAIN OUTCOME MEASURES: The primary outcome was reduction to normal cytology at 6 months after starting treatment. Secondary outcomes were clearance of high-risk human papilloma virus (hr-HPV) in both groups and reduction to ≤CIN1 in the imiquimod group. Side effects were monitored. RESULTS: Treatment success was 33% (6/18) in the imiquimod group versus 100% (16/16) in the LLETZ group (P < 0.001), whereas HPV clearance was 22% (4/18) in the imiquimod group versus 88% (14/16) in the LLETZ group (P < 0.001). After the randomisation of 35 women, the futility of treatment with imiquimod was proven and the trial was prematurely finished. In the follow-up period, three patients remained without additional treatment, whereas all other patients underwent LLETZ, conisation or hysterectomy. In the LLETZ group none of the patients received additional treatment during 2 years of follow-up. CONCLUSIONS: This is the first randomised controlled trial to show that topical imiquimod has a significantly lower success rate in terms of reduction to normal cytology and hr-HPV clearance, compared with LLETZ, in women with rrCIN. Additionally, imiquimod has numerous side effects and after using imiquimod most women with rrCIN still required additional surgical treatment.

COVID-19 in the Netherlands: lessons from a nationwide query of dutch autopsy, histology, and cytology pathological reports.

Since the onset of the COVID-19 pandemic, autopsies have played a valuable role in understanding the pathophysiology of COVID-19. In this study, we have analyzed COVID-19-related pathology reports from autopsies, histology, and cytology on a nationwide level. Pathology reports from all 43 pathology laboratories in the Netherlands stating "COVID," "Corona," and/or "SARS" were queried from the Dutch Nationwide Pathology Database (Palga). Consecutive reports of the included patients were also retrieved. Out of 5065 entries, a total of 1833 eligible COVID-19-related pathology reports between January 2020 and June 2021 were included in this collection of reports. Lung histopathology reports reflected differences in the severity of abnormalities (acute diffuse alveolar damage, alveolar histiocytes, and thrombi during the first three pandemic waves (Wuhan variant) versus the fourth wave (alpha variant)). Autopsy reports from 2020 state significantly shorter disease duration and younger age of death compared to autopsy reports from 2021. All reports together reflected a more granular pathology with comorbidities such as chronic histiocytic intervillositis, perniosis, and thrombi found in a variety of organs (lungs, kidneys, and small and large intestines). This nationwide overview of pathology reports provides data related to deaths as well as comorbidities in a clinical setting of COVID-19. Certain findings reported in SARS-CoV-infected lungs and placentas were also reported in post-COVID-19 tissue of the same kind. Consecutive reports after the earliest reports with COVID-19 allowed for follow-up reports. These follow-up reports can help with post-viral studies regarding long-term effects of COVID-19 as well as identifying the effects of different SARS-CoV-2 variants.

Clinical and Histopathological Risk Factors for Radioactive Iodine Refractory Follicular and Oncocytic Thyroid Carcinoma.

INTRODUCTION: Risk factors for radioactive iodine (RAI)-refractory disease in follicular (FTC) and oncocytic thyroid carcinoma (OTC) are unknown. Therefore, the aim of this study is to identify clinical and histopathological risk factors for RAI-refractory disease in FTC and OTC patients, facilitated by an extensive histopathological revision. METHODS: All adult FTC and OTC patients treated at Erasmus MC (the Netherlands) between 2000 and 2016 were retrospectively included. 2015 ATA Guidelines were used to define RAI-refractory disease. An extensive histopathological revision was performed applying the 2022 WHO Classification using Palga: Dutch Pathology Databank. Logistic regression was used to identify risk factors for RAI-refractory disease, stratified for histological subtype. RESULTS: Ninety FTC and 52 OTC patients were included, of which 14 FTC (15.6%) and 22 OTC (42.3%) developed RAI-refractory disease over a follow-up time of 8.5 years. RAI-refractory disease occurred in OTC after fewer cycles than in FTC (2.0 [IQR: 1.0-2.0] vs 2.5 [IQR: 2.0-3.75]), and it substantially decreased the 10-year disease specific survival, especially in OTC (46.4%; FTC 85.7%). In FTC, risk factors were higher age at diagnosis, pT3/pT4-stage, N1-stage, widely invasive tumors and extra-thyroidal extension. N1-stage and M1-stage were the strongest risk factors in OTC, rather than histopathological characteristics of the primary tumor. CONCLUSION: To our knowledge, this is the first study that correlates clinical and histopathological risk factors with RAI-refractory disease in FTC and OTC, facilitated by a histopathological revision. In FTC, risk factors for RAI-refractory disease were foremost histopathological characteristics of the primary tumor, whereas in OTC presentation with lymph node and distant metastasis was associated with RAI-refractory disease. Our data can help clinical decision making, particularly in patients at risk for RAI-refractory disease.

Increase in venous thromboembolism in SARS-CoV-2 infected lung tissue: proteome analysis of lung parenchyma, isolated endothelium, and thrombi.

AIMS: COVID-19 pneumonia is characterized by an increased rate of deep venous thrombosis and pulmonary embolism. To better understand the pathophysiology behind thrombosis in COVID-19, we performed proteomics analysis on SARS-CoV-2 infected lung tissue. METHODS: Liquid chromatography mass spectrometry was performed on SARS-CoV-2 infected postmortem lung tissue samples. Five protein profiling analyses were performed: whole slide lung parenchyma analysis, followed by analysis of isolated thrombi and endothelium, both stratified by disease (COVID-19 versus influenza) and thrombus morphology (embolism versus in situ). Influenza autopsy cases with pulmonary thrombi were used as controls. RESULTS: Compared to influenza controls, both analyses of COVID-19 whole-tissue and isolated endothelium showed upregulation of proteins and pathways related to liver metabolism including urea cycle activation, with arginase being among the top upregulated proteins in COVID-19 lung tissue. Analysis of isolated COVID-19 thrombi showed significant downregulation of pathways related to platelet activation compared to influenza thrombi. Analysis of isolated thrombi based on histomorphology shows that in situ thrombi have significant upregulation of coronavirus pathogenesis proteins. CONCLUSIONS: The decrease in platelet activation pathways in severe COVID-19 thrombi suggests a relative increase in venous thromboembolism, as thrombi from venous origin tend to contain fewer platelets than arterial thrombi. Based on histomorphology, in situ thrombi show upregulation of various proteins related to SARS-CoV-2 pathogenesis compared to thromboemboli, which may indicate increased in situ pulmonary thrombosis in COVID-19. Therefore, this study supports the increase of venous thromboembolism without undercutting the involvement of in situ thrombosis in severe COVID-19.

Interval post-colonoscopy colorectal cancer following a negative colonoscopy in a fecal immunochemical test-based screening program.

BACKGROUND: In the Dutch colorectal (CRC) screening program, fecal immunochemical test (FIT)-positive individuals are referred for colonoscopy. If no relevant findings are detected at colonoscopy, individuals are reinvited for FIT screening after 10 years. We aimed to assess CRC risk after a negative colonoscopy in FIT-positive individuals. METHODS: In this cross-sectional cohort study, data were extracted from the Dutch national screening information system. Participants with a positive FIT followed by a negative colonoscopy between 2014 and 2018 were included. A negative colonoscopy was defined as a colonoscopy during which no more than one nonvillous, nonproximal adenoma < 10 mm or serrated polyp < 10 mm was found. The main outcome was interval post-colonoscopy CRC (iPCCRC) risk. iPCCRC risk was reviewed against the risk of interval CRC after a negative FIT (FIT IC) with a 2-year screening interval. RESULTS: 35 052 FIT-positive participants had a negative colonoscopy and 24 iPCCRCs were diagnosed, resulting in an iPCCRC risk of 6.85 (95 %CI 4.60-10.19) per 10 000 individuals after a median follow-up of 1.4 years. After 2.5 years of follow-up, age-adjusted iPCCRC risk was approximately equal to FIT IC risk at 2 years. CONCLUSION: Risk of iPCCRC within a FIT-based CRC screening program was low during the first years after colonos-copy but, after 2.5 years, was the same as the risk in FIT-negative individuals at 2 years, when they are reinvited for screening. Colonoscopy quality may therefore require further improvement and FIT screening interval may need to be reduced after negative colonoscopy.

Colorectal Cancer Stage Distribution at First and Repeat Fecal Immunochemical Test Screening.

BACKGROUND & AIMS: For colorectal cancer (CRC) screening to be effective, it is important that screen-detected cancers are found at an early stage. Studies on stage distribution of screen-detected CRC at repeat screening of large population-based fecal immunochemical test (FIT)-based screening programs and the impact of FIT cut-off values on staging currently are lacking. METHODS: We obtained data for FIT-positive participants (FIT cut-off, 47 µg hemoglobin/g feces) at their first or second (ie, repeat) screening from the Dutch National Screening Database from 2014 to 2018. Tumor characteristics were acquired through linkage with The Netherlands Cancer Registry. We compared stage at diagnosis (I-II vs III-IV) of CRCs detected at a first or second screening. In addition, we analyzed the hypothetical yield and stage distribution of CRC for different FIT cut-off values up to 250 µg hemoglobin/g feces. RESULTS: At the first and second screenings, respectively, 15,755 and 3304 CRCs were detected. CRCs detected at the first or second screening were equally likely to be stages I to II (66.5% vs 67.7%; relative risk, 1.02; 95% CI, 1.00-1.05). A hypothetical increase of the FIT cut-off value from 47 µg to 250 µg resulted in a reduction of detected CRCs by 88.3% and 79.0% at the first or second screening, respectively. Even then, the majority of detected CRCs (63%-64%) still would be diagnosed at stages I to II. CONCLUSIONS: FIT-based screening is effective in downstaging CRC, and also at repeat screening. Increasingly, the FIT cut-off level has a limited impact on the stage distribution of detected CRCs, although it greatly affects CRC detection and thus is important to keep low.

The Role of the IGF2 Methylation Score in Diagnosing Adrenocortical Tumors with Unclear Malignant Potential-Feasibility of Formalin-Fixed Paraffin-Embedded Tissue.

The differentiation between benign and malignant adrenocortical tumors based on pathological assessment can be difficult. We present a series of 17 patients with unclear malignant tumors, of whom six had recurrent or metastatic disease. The assessment of the methylation pattern of insulin-like growth factor 2 (IGF2) regulatory regions in fresh frozen material has shown to be valuable in determining the malignancy of adrenocortical tumors, although this has not been elaborately tested in unclear malignant tumors. Since fresh frozen tissue was only available in six of the patients, we determined the feasibility of using formalin-fixed paraffin-embedded (FFPE) tissue for this method. We isolated DNA from FFPE tissue and matched the fresh frozen tissue of three patients with adrenocortical carcinoma. Methylation patterns of IGF2 regulatory regions were determined by pyrosequencing using different amounts of bisulfite-converted DNA (5 ng, 20 ng, 40 ng). Compared to fresh frozen tissue, FFPE tissue had a higher failure rate (fresh frozen 0%; FFPE 18.5%) and poor-to-moderate replicability (fresh frozen rho = 0.89-0.99, median variation 1.6%; FFPE rho = -0.09-0.85, median variation 7.7%). There was only a poor-to-moderate correlation between results from fresh frozen and FFPE tissue (rho = -0.28-0.70, median variation 13.2%). In conclusion, FFPE tissue is not suitable for determining the IGF2 methylation score in patients with an unclear malignant adrenocortical tumor using the currently used method. We, therefore, recommend fresh frozen storage of resection material for diagnostic and biobank purposes.

European experience with the Afirma Gene Expression Classifier for indeterminate thyroid nodules: A clinical utility study in the Netherlands.

BACKGROUND: The Gene Expression Classifier (GEC) and Genomic Sequencing Classifier (GSC) were developed to improve risk stratification of indeterminate nodules. Our aim was to assess the clinical utility in a European population with restrictive diagnostic workup. METHODS: Clinical utility of the GEC was assessed in a prospective multicenter cohort of 68 indeterminate nodules. Diagnostic surgical rates for Bethesda III and IV nodules were compared to a historical cohort of 171 indeterminate nodules. Samples were post hoc tested with the GSC. RESULTS: The GEC classified 26% as benign. Surgical rates between the prospective and historical cohort did not differ (72.1% vs. 76.6%). The GSC classified 59% as benign, but misclassified six malignant lesions as benign. CONCLUSION: Implementation of GEC in management of indeterminate nodules in a European country with restrictive diagnostic workup is currently not supported, especially in oncocytic nodules. Prospective studies with the GSC in European countries are needed to determine the clinical utility.

Socio-demographic and cultural factors related to non-participation in the Dutch colorectal cancer screening programme.

BACKGROUND: High participation rates are essential for a screening programme to be beneficial. To reach non-participants in a targeted manner, insight in characteristics of non-participants is needed. We investigated demographic differences between participants and non-participants in the Dutch faecal immunochemical test-based colorectal cancer (CRC) screening programme. METHODS: In this population-based cohort study, we included all invitees for CRC screening in 2018 and 2019. Participation status, birth year, and sex were extracted from the Dutch national screening information system and linked to demographic characteristics from Statistics Netherlands, including migration background, level of education, socioeconomic category, household composition, and household income. A multivariable logistic regression was used to assess the association between demographic factors and participation. RESULTS: A total of 4,383,861 individuals were invited for CRC screening in 2018 and 2019, of which 3,170,349 (72.3%) participated. Individuals were less likely to participate when they were single and/or living with others (single with other residents versus couple: odds ratio [OR] 0.34, 95% confidence interval [CI]: 0.31-0.38), had a migration background (e.g. Moroccan migrant versus Dutch background: OR 0.43, 95% CI: 0.42-0.44), or had a low income (lowest versus highest quintile: OR 0.45, 95% CI: 0.44-0.45). Although to a lesser extent, non-participation was also significantly associated with being male, being younger, receiving social welfare benefits and having a low level of education. CONCLUSION: We found that individuals who were single and/or living with others, immigrants from Morocco or individuals with low income were the least likely to participate in the Dutch CRC screening programme. Targeted interventions are needed to minimise inequities in CRC screening.

Tumor size and presence of metastases in differentiated thyroid cancer: comparing cohorts from two countries.

OBJECTIVE: Incidence of thyroid cancer varies widely, even across neighboring countries. Data on this phenomenon are largely lacking but are likely related to differences in health care systems. Therefore, we explored whether there are differences between populations from these 2 countries with respect to the relationship between tumor size and advanced disease. METHODS: We retrospectively studied 2 cohorts of adult differentiated thyroid cancer (DTC) patients from a Dutch and a German university hospital. We analyzed the presence of lymph node metastases with respect to tumor size for papillary thyroid cancer (PTC), and the presence of distant metastases for DTC, and PTC and follicular thyroid cancer (FTC) separately. RESULTS: We included 1771 DTC patients (80% PTC, 20% FTC; 24% lymph node and 8% distant metastases). For PTC, the proportion of patients with lymph node metastases was significantly higher in the Dutch than in the German population for tumors ≤ 1 cm (45% vs. 14%; P < .001). For DTC, distant metastases occurred particularly significantly more frequently in the Dutch than in the German population for tumors ≤ 2 cm (7% vs. 2%; P = .004). CONCLUSION: The presence of lymph node and distant metastases is significantly higher in pT1 DTC cases in the Dutch compared to the German cohort, which might be caused by differences in the indication for and application of diagnostic procedures eventually leading to DTC diagnosis. Our results implicate that one should be cautious when extrapolating results and guidelines from 1 country to another.

Impact of delayed screening invitations on screen-detected and interval cancers in the Dutch colorectal cancer screening programme: individual-level data analysis.

OBJECTIVE: To assess the impact of delayed invitation on screen-detected and interval colorectal cancers (CRC) within a faecal immunochemical testing (FIT)-based CRC screening programme. DESIGN: All individuals that participated in 2017 and 2018 with a negative FIT and were eligible for CRC screening in 2019 and 2020 were included using individual-level data. Multivariable logistic regression analyses were used to assess the association between either the different time periods (ie, 'before', 'during' and 'after' the first COVID-19 wave) or the invitation interval on screen-detected and interval CRCs. RESULTS: Positive predictive value for advanced neoplasia (AN) was slightly lower during (OR=0.91) and after (OR=0.95) the first COVID-19 wave, but no significant difference was observed for the different invitation intervals. Out of all individuals that previously tested negative, 84 (0.004%) had an interval CRC beyond the 24 months since their last invitation. The time period of invitation as well as the extended invitation interval was not associated with detection rates for AN and interval CRC rate. CONCLUSION: The impact of the first COVID-19 wave on screening yield was modest. A very small proportion of the FIT negatives had an interval CRC possibly due to an extended interval, which potentially could have been prevented if they had received the invitation earlier. Nonetheless, no increase in interval CRC rate was observed, indicating that an extended invitation interval up to 30 months had no negative impact on the performance of the CRC screening programme and a modest extension of the invitation interval seems an appropriate intervention.

Evaluation of DNA methylation biomarkers ASCL1 and LHX8 on HPV-positive self-collected samples from primary HPV-based screening.

BACKGROUND: Host-cell DNA methylation analysis can be used to triage women with high-risk human papillomavirus (HPV)-positive self-collected cervicovaginal samples, but current data are restricted to under-/never-screened women and referral populations. This study evaluated triage performance in women who were offered primary HPV self-sampling for cervical cancer screening. METHODS: Self-collected samples from 593 HPV-positive women who participated in a primary HPV self-sampling trial (IMPROVE study; NTR5078), were tested for the DNA methylation markers ASCL1 and LHX8 using quantitative multiplex methylation-specific PCR (qMSP). The diagnostic performance for CIN3 and cervical cancer (CIN3 + ) was evaluated and compared with that of paired HPV-positive clinician-collected cervical samples. RESULTS: Significantly higher methylation levels were found in HPV-positive self-collected samples of women with CIN3 + than control women with no evidence of disease (P values <0.0001). The marker panel ASCL1/LHX8 yielded a sensitivity for CIN3 + detection of 73.3% (63/86; 95% CI 63.9-82.6%), with a corresponding specificity of 61.1% (310/507; 95% CI 56.9-65.4%). The relative sensitivity for detecting CIN3+ was 0.95 (95% CI 0.82-1.10) for self-collection versus clinician-collection, and the relative specificity was 0.82 (95% CI 0.75-0.90). CONCLUSIONS: The ASCL1/LHX8 methylation marker panel constitutes a feasible direct triage method for the detection of CIN3 + in HPV-positive women participating in routine screening by self-sampling.

Early effect of bivalent human papillomavirus vaccination on cytology outcomes in cervical samples among young women in the Netherlands.

BACKGROUND: The first HPV-vaccine eligible cohorts in the Netherlands will enter the cervical screening program in 2023. However, a substantial number of young women already have had a cervical sample taken before entry into the regular screening program. This study was initiated to explore early effects of HPV vaccination on detection of cytological abnormalities in cervical samples of women younger than the screening age. METHODS: Results of cervical samples were obtained from the Dutch National Pathology Databank (PALGA) and were linked to the women's HPV vaccination status from the national vaccination registry (Praeventis) (N = 42,171). Occurrence of low-grade and high-grade squamous intraepithelial lesions or worse (LSIL and HSIL+) and high-risk HPV positive tests (hrHPV) in the first cervical sample were compared between vaccinated and unvaccinated women by multivariable logistic regression analysis, corrected for age at cervical sampling and age of vaccination (12/13 years, ≥ = 14 years). RESULTS: For fully vaccinated women (three- or two-dose schedule), statistically significant reductions were seen for all outcomes compared to unvaccinated women (hrHPV: adjusted OR, 0.70, 95% CI, 0.63-0.79; LSIL: 0.70, 0.61-0.80; HSIL+: 0.39, 0.30-0.51). CONCLUSIONS: By linking nation-wide registries on pathology and vaccination, we show significant beneficial early effects of HPV-vaccination on LSIL, HSIL+, CIN3/AIS/carcinoma and hrHPV detection in young women upto 24 years of age who have a cervical sample taken before entry into the cervical cancer screening program.

Personalized colorectal cancer screening: study protocol of a mixed-methods study on the effectiveness of tailored intervals based on prior f-Hb concentration in a fit-based colorectal cancer screening program (PERFECT-FIT).

BACKGROUND: In 2014, the national population-based colorectal cancer (CRC) screening program was implemented in the Netherlands. Biennial fecal immunochemical testing (FIT) for hemoglobin (Hb) is used at a cut-off of 47 µg Hb per gram feces. The CRC screening program successfully started, with high participation rates and yield of screening. Now that the program has reached a steady state, there is potential to further optimize the program. Previous studies showed that prior fecal Hb (f-Hb) concentrations just below the FIT cut-off are associated with a higher risk for detection of advanced neoplasia (AN) at subsequent screening rounds. We aim to achieve a better balance between the harms and benefits of CRC screening by offering participants tailored invitation intervals based on prior f-Hb concentrations after negative FIT. METHODS: This mixed-methods study will be performed within the Dutch national CRC screening program and will consist of: (1) a randomized controlled trial (RCT), (2) focus group studies, and (3) decision modelling. The primary outcome is the yield of AN per screened individual in personalized screening vs. uniform screening. Secondary outcomes are perspectives on, acceptability of and adherence to personalized screening, as well as long-term outcomes of personalized vs. uniform screening. The RCT will include 20,000 participants of the Dutch CRC screening program; 10,000 in the intervention and 10,000 in the control arm. The intervention arm will receive a personalized screening interval based on the prior f-Hb concentration (1, 2 or 3 years). The control arm will receive a screening interval according to current practice (2 years). The focus group studies are designed to understand individuals' perspectives on and acceptability of personalized CRC screening. Results of the RCT will be incorporated into the MISCAN-Colon model to determine long-term benefits, harms, and costs of personalized vs. uniform CRC screening. DISCUSSION: The aim of this study is to evaluate the yield, feasibility, acceptability and (cost-) effectiveness of personalized CRC screening through tailored invitation intervals based on prior f-Hb concentrations. This knowledge may be of guidance for health policy makers and may provide evidence for implementing personalized CRC screening in The Netherlands and/or other countries using FIT as screening modality. TRIAL REGISTRATION: ClinicalTrials.gov, NCT05423886, June 21, 2022, https://clinicaltrials.gov/ct2/show/NCT05423886.

Identification of over- and undertreatment in the Dutch national cervical cancer screening program: A data linkage study at the hospital level.

Research into the quality of cancer screening programs often lacks the perspective of clinicians, missing insights into the performance of individual hospitals. This retrospective cohort study aimed to identify guideline deviation (specifically, overtreatment and undertreatment) related to the cervical cancer screening program in Dutch hospitals by deterministically linking nationwide insurance data with pathology data for cervical intraepithelial neoplasia (CIN). We then constructed quality indicators using the Dutch CIN guideline and National Health Care Institute recommendations to assess compliance with CIN management, treatment outcomes, and follow-up, using an empirical Bayes shrinkage model to correct for case-mix variation and hospitals with few observations. Data were linked for 115,899 of 125,751 (92%) eligible women. Overtreatment was observed in the see-and-treat approach (immediate treatment) for women with low-grade referral cytology (4%; hospital range, 0%-25%), CIN ≤ 1 treatment specimens (26%; hospital range, 10%-55%), and follow-up cervix cytology ≥2 months before the guideline recommendation after treatment for CIN 2 (2%; hospital range, 0%-9%) or CIN 3 (5%; hospital range, 0%-19%). By contrast, undertreatment was observed for treatment within 3 months after a CIN 3 biopsy result (90%; hospital range 59%-100%) and follow-up ≥2 months beyond the guideline recommendation after treatments for CIN 2 (21%, hospital range 7%-48%) and CIN 3 (20%, hospital range 7%-90%). In conclusion, we found evidence of CIN overtreatment and undertreatment in all measured domains at the hospital level. Guideline adherence could be improved by implementing the developed indicators in an audit and feedback instrument for use by healthcare professionals in routine practice.

Advanced-stage CRC incidence patterns following the phased implementation of the CRC screening programme in the Netherlands.

BACKGROUND AND AIMS: From 2014, the Dutch colorectal cancer (CRC) faecal immunochemical testing-based screening programme was gradually rolled out by birth cohort. We evaluated changes in advanced-stage CRC incidence by timing of invitation to further strengthen the evidence for the effectiveness of CRC screening. METHODS: Data on advanced-stage CRC incidence in the period 2010-2019 by invitation cohort were collected through the Netherlands Cancer Registry. Crude rates of advanced-stage CRC incidence and cumulative advanced-stage CRC incidence were calculated. Observed advanced-stage CRC incidence and cumulative advanced-stage CRC incidence were compared with expected advanced-stage CRC incidence and cumulative advanced-stage CRC incidence by invitation cohort using trend lines extrapolating data prior to the introduction of screening. RESULTS: For the invitation cohort that was first invited for screening in 2014, advanced-stage CRC incidence increased before the introduction of screening from 94.1 to 124.7 per 100,000 individuals in the period 2010-2013. In 2014, the observed increase was higher than in preceding years, to 184.9 per 100,000 individuals. Hereafter, a decrease in incidence was observed to levels below expected incidence based on trends before the introduction of screening. A similar pattern was observed for invitation cohorts in subsequent years, coinciding with the first invitation to the screening programme. In 2019, the observed incidence for all invitation cohorts remained below expected incidence. The cumulative advanced-stage CRC incidence in the 2014-2016 invitation cohorts was significantly lower than the expected cumulative CRC incidence in the period 2010-2019. CONCLUSIONS: In the period 2014-2019, an increase in advanced-stage CRC incidence was observed for all invitation cohorts first invited for screening, followed by a decrease below expected incidence, following the pattern of the phased implementation. The cumulative advanced-stage CRC incidence in invitation cohorts invited for screening multiple times was lower than expected based on trends from the pre-screening era. These findings support a causal relationship between the introduction of the Dutch screening programme and a decrease in advanced-stage CRC incidence.

Feasibility and Potential of Transcriptomic Analysis Using the NanoString nCounter Technology to Aid the Classification of Rejection in Kidney Transplant Biopsies.

BACKGROUND: Transcriptome analysis could be an additional diagnostic parameter in diagnosing kidney transplant (KTx) rejection. Here, we assessed feasibility and potential of NanoString nCounter analysis of KTx biopsies to aid the classification of rejection in clinical practice using both the Banff-Human Organ Transplant (B-HOT) panel and a customized antibody-mediated rejection (AMR)-specific NanoString nCounter Elements (Elements) panel. Additionally, we explored the potential for the classification of KTx rejection building and testing a classifier within our dataset. METHODS: Ninety-six formalin-fixed paraffin-embedded KTx biopsies were retrieved from the archives of the ErasmusMC Rotterdam and the University Hospital Cologne. Biopsies with AMR, borderline or T cell-mediated rejections (BLorTCMR), and no rejection were compared using the B-HOT and Elements panels. RESULTS: High correlation between gene expression levels was found when comparing the 2 chemistries pairwise (r = 0.76-0.88). Differential gene expression (false discovery rate; P < 0.05) was identified in biopsies diagnosed with AMR (B-HOT: 294; Elements: 76) and BLorTCMR (B-HOT: 353; Elements: 57) compared with no rejection. Using the most predictive genes from the B-HOT analysis and the Element analysis, 2 least absolute shrinkage and selection operators-based regression models to classify biopsies as AMR versus no AMR (BLorTCMR or no rejection) were developed achieving an receiver-operating-characteristic curve of 0.994 and 0.894, sensitivity of 0.821 and 0.480, and specificity of 1.00 and 0.979, respectively, during cross-validation. CONCLUSIONS: Transcriptomic analysis is feasible on KTx biopsies previously used for diagnostic purposes. The B-HOT panel has the potential to differentiate AMR from BLorTCMR or no rejection and could prove valuable in aiding kidney transplant rejection classification.

Factors associated with interval colorectal cancer after negative FIT: Results of two screening rounds in the Dutch FIT-based CRC screening program.

The interval colorectal cancer (CRC) rate after negative fecal immunochemical testing (FIT) is an important quality indicator of CRC screening programs. We analyzed the outcomes of two rounds of the FIT-based CRC screening program in the Netherlands, using data from individuals who participated in FIT-screening from 2014 to 2017. Data of individuals with one prior negative FIT (first round) or two prior negative FITs (first and second round) were included. Outcomes included the incidence of interval CRC in FIT-negative participants (<47 µg Hb/g feces [µg/g]), FIT-sensitivity, and the probability of detecting an interval CRC by fecal hemoglobin concentration (f-Hb). FIT-sensitivity was estimated using the detection method and the proportional incidence method (based on expected CRC incidence). Logistic regression analysis was performed to estimate whether f-Hb affects probability of detecting interval CRC, adjusted for sex- and age-differences. Incidence of interval CRC was 10.4 per 10 000 participants after the first and 9.6 after the second screening round. FIT-sensitivity based on the detection method was 84.4% (95%CI 83.8-85.0) in the first and 73.5% (95% CI 71.8-75.2) in the second screening round. The proportional incidence method resulted in a FIT-sensitivity of 76.4% (95%CI 73.3-79.6) in the first and 79.1% (95%CI 73.7-85.3) in the second screening round. After one negative FIT, participants with f-Hb just below the cut-off (>40-46.9 µg/g) had a higher probability of detecting an interval CRC (OR 16.9; 95%CI: 14.0-20.4) than had participants with unmeasurable f-Hb (0-2.6 µg/g). After two screening rounds, the odds ratio for interval CRC was 12.0 (95%CI: 7.8-17.6) for participants with f-Hb just below the cut-off compared with participants with unmeasurable f-Hb. After both screening rounds, the Dutch CRC screening program had a low incidence of interval CRC and an associated high FIT-sensitivity. Our findings suggest there is a potential for further optimizing CRC screening programs with the use of risk-stratified CRC screening based on prior f-Hb.