Johannes Berkhof

Amsterdam University Medical Center | VUmc · Department of Epidemiology and Biostatistics

Recently, the immunohistochemical markers cytokeratin 17 (CK17) and SRY-box2 (SOX2) have been evaluated as adjuncts for the diagnosis of high-grade vulvar intraepithelial neoplasia (VIN). In the present study, the aim was to assess CK17 and SOX2 expression in VIN by studying 150 vulvar lesions, originally reported as high-grade VIN and to assess th...

Objectives The leukodystrophy “vanishing white matter” (VWM) and “metachromatic leukodystrophy” (MLD) affect the brain's white matter, but have very different underlying pathology. We aim to determine whether quantitative MRI reflects known neuropathological differences and correlates with clinical scores in these leukodystrophies. Methods VWM and...

Molecular testing for human papillomaviruses (HPV) is gradually replacing cytology in cervical cancer screening. In this longitudinal population‐based cohort study, 4140 women 20 to 64 years old attending organized screening were tested at baseline by five different screening methods and followed for 9 years. To assess long‐term safety, the cumulat...

While HC2 and GP5+/6+ PCR‐EIA were pivotal in test validation of new HPV assays, they represent the first generation of comparator tests based upon technologies that are not in widespread use anymore. In the current guideline, criteria for second‐generation comparator tests are presented that include more detailed resolution of HPV genotypes. Secon...

To optimize colorectal cancer (CRC) surveillance, accurate information on the risk of developing CRC from premalignant lesions is essential. However, directly observing this risk is challenging since precursor lesions, i.e., advanced adenomas (AAs), are removed upon detection. Statistical methods for multistate models can estimate risks, but estima...

With the advent of the first generation of disease‐modifying treatments for Alzheimer's disease, it is clearer now more than ever that the field needs to move toward personalized medicine. Pooling data from past trials may help identify subgroups most likely to benefit from specific treatments and thus inform future trial design. In this perspectiv...

Background and objectives: Cognitive decline rates in Alzheimer disease (AD) vary greatly. Disease-modifying treatments may alter cognitive decline trajectories, rendering their prediction increasingly relevant. We aimed to construct clinically applicable prediction models of cognitive decline in amyloid-positive patients with mild cognitive impai...

Cervical cancer screening programs, including triage tests, need redesigning as human papillomavirus (HPV)‐vaccinated women are entering the programs. Methylation markers offer a potential solution to reduce false‐positive rates by identifying clinically relevant cervical lesions with progressive potential. In a nested case–control study, 9242 wome...

Background The use of amyloid-PET in dementia workup is upcoming. At the same time, amyloid-PET is costly and limitedly available. While the appropriate use criteria (AUC) aim for optimal use of amyloid-PET, their limited sensitivity hinders the translation to clinical practice. Therefore, there is a need for tools that guide selection of patients...

Background High-risk human papillomavirus (hrHPV)-based cervical cancer screening in the Netherlands led to a substantial increase in number of colposcopy referrals and low-grade lesions detected. Genotyping strategies may be employed to lower the screening-related burden. Methods We evaluated 14 triage strategies with genotyping (HPV16/18 or HPV1...

Objectives Investigate the results and usability of the Vineland‐3 as an outcome measure in vanishing white matter patients. Methods A cross‐sectional investigation of the Vineland‐3 based on interviews with caregivers, the Health Utilities Index, and the modified Rankin Scale in 64 vanishing white matter patients. Results Adaptive behavior measu...

Objectives Human papillomavirus (HPV)–independent vulvar intraepithelial neoplasia (VIN) is a rare yet aggressive precursor lesion of vulvar cancer. Our objectives were to estimate its long-term incidence, the risk of recurrent disease and progression to vulvar cancer, and risk factors thereof. Materials and Methods Patients with HPV-independent V...

Background Most European countries offer human papillomavirus (HPV) vaccination through organized immunisation programmes, but the choice of vaccine varies. We compared the expected health and economic effects of the currently used bivalent vaccine, targeting HPV-16/18, and the nonavalent vaccine, targeting seven additional genotypes, for the Nethe...

Background Cognitive decline rates in Alzheimer’s disease (AD) vary greatly. Disease‐modifying treatments (DMT) may alter cognitive decline trajectories, rendering their prediction increasingly relevant. We aimed to construct clinically applicable prediction models of cognitive decline in amyloid‐positive patients with mild cognitive impairment (MC...

Background To estimate the perceived value of additional testing with amyloid-PET in Euros in healthy participants acting as analogue patients with mild cognitive impairment (MCI). Methods One thousand four hundred thirty-one healthy participants acting as analogue MCI patients (mean age 65 ± 8, 929 (75%) female) were recruited via the Dutch Brain...

Background Cervical cancer is a major public health problem in India, where access to prevention programmes is low. The WHO-Strategic Advisory Group of Experts recently updated their recommendation for human papillomavirus (HPV) vaccination to include a single-dose option in addition to the two-dose option, which could make HPV vaccination programm...

Background Minimally invasive pancreatoduodenectomy (MIPD) aims to reduce the negative impact of surgery as compared to open pancreatoduodenectomy (OPD) and is increasingly becoming part of clinical practice for selected patients worldwide. However, the safety of MIPD remains a topic of debate and the potential shorter time to functional recovery n...

Aims Adequate diagnosis of human papillomavirus (HPV)‐associated high‐grade squamous intraepithelial lesion (HSIL) and HPV‐independent vulvar intraepithelial neoplasia (VIN) is essential but can be challenging. We comprehensively characterized a large population‐based series of vulvar lesions, originally reported as high‐grade VIN, and assessed the...

We spoke to Dr Johannes Berkhof, the coordinator of the RISCC project which aims to develop a risk-based approach to screening for cervical cancer, using screening history and other risk factors.

Background: The leukodystrophy "Vanishing White Matter" (VWM) is an orphan disease with neurological decline and high mortality. Currently, VWM has no approved treatments, but advances in understanding pathophysiology have led to identification of promising therapies. Several investigational medicinal products are either in or about to enter clini...

Women treated for CIN2/3 remain at increased risk of recurrent CIN and cervical cancer, and therefore posttreatment surveillance is recommended. This post hoc analysis evaluates the potential of methylation markers ASCL1/LHX8 and FAM19A4/miR124‐2 for posttreatment detection of recurrent CIN2/3. Cervical scrapes taken at 6 and 12 months posttreatmen...

Background Minimally invasive pancreatoduodenectomy (MIPD) aims to reduce the negative impact of surgery as compared to open pancreatoduodenectomy (OPD) and is increasingly becoming part of clinical practice for selected patients worldwide. However, the safety of MIPD remains a topic of debate and the potential shorter time to functional recovery n...

Importance: Amyloid positron emission tomography (PET) allows the direct assessment of amyloid deposition, one of the main hallmarks of Alzheimer disease. However, this technique is currently not widely reimbursed because of the lack of appropriately designed studies demonstrating its clinical effect. Objective: To assess the clinical effect of...

Objective: Adaptive designs may reduce trial sample sizes and costs. This study illustrates a Bayesian adaptive decision-theoretic design applied to a multi-arm exercise oncology trial. Study design and setting: In the PACES trial, 230 breast cancer patients receiving chemotherapy were randomized to supervised resistance and aerobic exercise (On...

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 c...

Introduction: We evaluated determinants associated with care partner outcomes along the Alzheimer's disease (AD) stages. Methods: We included n = 270 care partners of amyloid-positive patients in the pre-dementia and dementia stages of AD. Using linear regression analysis, we examined determinants of four care partner outcomes: informal care tim...

The precursor lesions of vulvar squamous cell carcinoma (VSCC) include human papillomavirus (HPV)‐associated and HPV‐independent squamous neoplasia with a varying cancer risk. Our study aimed to validate the accuracy of previously identified DNA methylation markers for detection of such high‐grade vulvar intraepithelial neoplasia (VIN). A large cli...

Background Cervical cancer is a major public health problem in India, where access to prevention programmes is low. The World Health Organization-Strategic Advisory Group of Experts recently updated their recommendation for human papillomavirus (HPV) vaccination to include a single-dose option in addition to the two-dose option, which could make HP...

Background: Treatment options for patients with recurrent glioblastoma (rGBM) are limited. The lack of effectiveness from oral multi-targeted tyrosine kinase inhibitors, like sunitinib, might be due to a restricted blood-brain barrier penetration. We previously found that standard daily dosed sunitinib resulted in relatively low tumor drug concentr...

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 cytologi...

Importance Individuals who are amyloid-positive with subjective cognitive decline and clinical features increasing the likelihood of preclinical Alzheimer disease (SCD+) are at higher risk of developing dementia. Some individuals with SCD+ undergo amyloid-positron emission tomography (PET) as part of research studies and frequently wish to know the...

Background: The leukodystrophy “Vanishing White Matter” (VWM) is an orphan disease with neurological decline and high mortality. Currently, VWM has no approved treatments, but advances in understanding pathophysiology have led to identification of promising therapies. Several investigational medicinal products are either in or about to enter clinic...

Introduction: We studied life satisfaction across Alzheimer's disease (AD) stages and studied mobility and meaningful activities as mediators of the associations between these AD stages and life satisfaction. Methods: In this cross-sectional study, we included n = 269 amyloid-positive patients with subjective cognitive decline (SCD), mild cognit...

Quality of life (QoL) is an important outcome from the perspective of patients and their caregivers, in both dementia and pre‐dementia stages.1 Yet, little is known about the long‐term changes in QoL over time.2 We aimed to compare the trajectories of the QoL between amyloid‐positive and amyloid‐negative patients along the Alzheimer’s disease (AD)...

Amyloid‐PET allows the direct assessment of amyloid deposition, one of the main hallmarks of Alzheimer’s disease. However, this technique is currently not or incompletely reimbursed due to lack of randomized controlled studies demonstrating a clinical impact. AMYPAD‐DPMS is a prospective, multicenter, randomized controlled study. Patients with subj...

Amyloid‐PET allows the assessment of amyloid deposition, one of the main hallmarks of Alzheimer’s disease. However, in most countries, this exam is not routinely used in clinical practice. Several studies have assessed physician‐centered outcomes, yet often without a randomized study design. In addition, the choice to reimburse amyloid‐PET depends...

The current study describes the long-term effectiveness of three-dose HPV16/18 vaccination among Dutch women who were eligible for vaccination during a catch-up campaign and were followed in an observational cohort study. Ten years post vaccination, vaccine effectiveness (VE) was estimated using generalized estimating equation models. VE against pe...

Background: The invasive microvascular function indices, coronary flow reserve (CFR) and the index of microcirculatory resistance (IMR), exhibit a dynamic pattern after ST-segment-elevation myocardial infarction. The effects of microvascular injury on the evolution of the microvascular function and the prognostic significance of the evolution of m...

Background Human papillomavirus (HPV)-based screening programs still use one-size-fits-all protocols but efficiency and efficacy of programs may be improved by stratifying women based on previous screening results. Methods and findings We studied the association between cervical intraepithelial neoplasia grade 3 or cancer (CIN3+) and previous scre...

Introduction/Background Cervical screening can prevent cancer by detection and treatment of cervical intraepithelial neoplasia grade 2 or 3 (CIN2/3). Screening also results in considerable overtreatment possibly causing complications, unnecessary anxiety and costs, and preterm birth because many CIN2/3 lesions show spontaneous regression when left...

Background Quality of life (QoL) is an important outcome from the perspective of patients and their caregivers, in both dementia and pre-dementia stages. Yet, little is known about the long-term changes in QoL over time. We aimed to compare the trajectories of QoL between amyloid-positive and amyloid-negative SCD or MCI patients and to evaluate QoL...

Background: In the Netherlands, lower high-risk human papillomavirus (hrHPV) positivity but higher cervical intraepithelial neoplasia (CIN)2+ detection were found in self-collected compared with clinician-collected samples. To investigate the possible reason for these differences, we compared sociodemographic and screening characteristics of women...

Background Despite the high burden of cervical cancer, access to preventive measures remains low in India. A single-dose immunisation schedule could facilitate the scale-up of human papillomavirus (HPV) vaccination, contributing to global elimination of cervical cancer. We projected the effect of single-dose quadrivalent HPV vaccination in India in...

Background: Patients and caregivers express a desire for accurate prognostic information about time to institutionalization and mortality. Previous studies predicting institutionalization and mortality focused on the dementia stage. However, Alzheimer's disease (AD) is characterized by a long pre-dementia stage. Therefore, we developed prediction...

Introduction Anal cancer precursors, or high-grade anal intraepithelial neoplasia (HGAIN), are highly prevalent in HIV-seropositive (HIV+) men who have sex with men (MSM). Around 30% of lesions regress within 1 year, but current histopathological assessment is unable to distinguish between HGAIN likely to regress and HGAIN likely to persist or prog...

Introduction: Randomized controlled trials (RCTs) yield the highest level of evidence but are notoriously difficult to perform in surgery. Surgical RCTs may be hampered by slow accrual, the surgical learning curve, and lack of financial support. Alternative RCT designs such as stepped-wedge RCTs (SW-RCTs), registry-based RCTs (RB-RCTs), and trials...

Background To optimize colorectal cancer (CRC) screening and surveillance, information regarding the time-dependent risk of advanced adenomas (AA) to develop into CRC is crucial. However, since AA are removed after diagnosis, the time from AA to CRC cannot be observed in an ethically acceptable manner. We propose a statistical method to indirectly...

Background and aim Human papillomavirus (HPV) testing has been recommended by the WHO as the first choice method in cervical cancer screening. So far, only a limited number of countries have implemented primary HPV testing, partly because of the assumed high costs of HPV testing. We assessed tender-based prices of HPV testing in Italy, where progra...

Background Cervical cancer screening tests that identify DNA of the main causal agent, high-risk human papillomavirus (HPV) types, are more protective than cervical cytology. We systematically reviewed the literature to assess whether tests targeting high-risk HPV (hrHPV) mRNA are as accurate and effective as HPV DNA-based screening tests. Methods...

Introduction: AMYPAD Diagnostic and Patient Management Study (DPMS) aims to investigate the clinical utility and cost-effectiveness of amyloid-PET in Europe. Here we present participants' baseline features and discuss the representativeness of the cohort. Methods: Participants with subjective cognitive decline plus (SCD+), mild cognitive impairm...

PURPOSE Cervical screening can prevent cancer by detection and treatment of cervical intraepithelial neoplasia grade 2 or 3 (CIN2/3). Screening also results in considerable overtreatment because many CIN2/3 lesions show spontaneous regression when left untreated. In this multicenter longitudinal cohort study of women with untreated CIN2/3, the prog...

Little is known about the long-term association between high-risk human papillomavirus (hrHPV) test results in women participating in a hrHPV-based cervical cancer screening program. To address this question, we collected data of 2217 women who participated in the POBASCAM hrHPV-based screening trial (enrolment 1999/2002) and also attended the Dutc...

Background Patients and care partners express a desire for accurate prognostic information. Previous studies predicting institutionalization and mortality focused on the dementia stage. Yet, Alzheimer’s disease (AD) is characterized by a long pre‐dementia stage. We aimed to predict institutionalization and mortality in patients across the cognitive...

Background AMYPAD‐DPMS is a European, multicenter, prospective, interventional, randomized controlled study. It aims to assess clinical utility and cost‐effectiveness of amyloid‐PET. It recruited individuals with Subjective Cognitive Decline plus (SCD+), and syndromic diagnosis of Mild Cognitive Impairment (MCI) and dementia. Here, we describe the...

(Abstracted from N Engl J Med 2021;385:1908–1918) In May 2018, the World Health Organization (WHO) called for the elimination of global cervical cancer as a major public health priority, with a 2-pronged approach focusing on effective vaccination against human papillomavirus (HPV) and the screening for and treatment of early cervical cancer. Cervic...

Background: Despite successful primary percutaneous coronary intervention (PCI), the restoration of the microvascular flow fails in up to 50% of the reperfused ST-segment elevation myocardial infarction (STEMI) patients, worsening the prognosis. This study aims to identify how post-STEMI microvascular function indices evolve over 1-month and how th...

Background The introduction of primary HPV screening has doubled the number of colposcopy referrals because of the direct referral of HPV-positive women with a borderline or mild dyskaryosis (BMD) cytology (ASC-US/LSIL) triage test. Further risk-stratification is warranted to improve the efficiency of HPV-based screening. Methods This study evalua...

Background High-risk human papillomavirus (hrHPV) testing on self-collected samples has potential as a primary screening tool in cervical screening, but real-world evidence on its accuracy in hrHPV-based screening programmes is lacking. Methods In the Netherlands, women aged 30–60 years invited for cervical screening can choose between sampling at...

Methylation of host‐cell deoxyribonucleic acid (DNA) has been proposed as a promising biomarker for triage of high‐risk (hr) human papillomavirus (HPV) positive women at screening. Our study aims to validate recently identified host‐cell DNA methylation markers for triage in an hrHPV‐positive cohort derived from primary HPV‐based cervical screening...

Background The restoration of the coronary microcirculation in ST-segment elevation myocardial infarction (STEMI) patients remains hampered in up to 50% of the STEMI patients after successful primary percutaneous coronary intervention (PCI). The association between the coronary microvascular function and injury indicators and functional outcome rem...

Background Myocardial infarction (MI) leads to complex changes in left ventricular (LV) haemodynamics. It remains unknown how four-dimensional (4D) acute changes in LV blood flow kinetic energy (KE) affect LV remodeling. We hypothesized that LV blood flow energetics are independently associated with adverse LV-remodeling. Methods In total, 69 reva...

Women infected by the Human papilloma virus are at an increased risk to develop cervical intraepithalial neoplasia lesions (CIN). CIN are classified into three grades of increasing severity (CIN-1, CIN-2, and CIN-3) and can eventually develop into cervical cancer. The main purpose of screening is detecting CIN-2 and CIN-3 cases which are usually tr...

Objectives The prognostic advantage of human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC) resulted in the initiation of treatment de-intensification studies. Two randomized controlled trials (RCTs) reported inferior survival of HPV-positive OPSCC treated with radiotherapy plus cetuximab compared to standard of care ra...

Before a new screening test can be used in routine screening, its performance needs to be compared to the standard screening test. This comparison is generally done in population screening trials with a screen‐positive design where participants undergo one or both screening tests after which disease verification takes place for those positive on at...

The licensed HPV vaccines are highly efficacious and induce high levels of neutralizing antibody levels, the assumed mediators of protection. However, a correlate of protection against HPV is lacking, and the evidence is still limited as to long-term persistence of antibodies, especially following reduced dosing schedules. The World Health Organiza...

High‐grade cervical intraepithelial neoplasia (CIN2 and CIN3) represents a heterogeneous disease with varying cancer progression risks. Biomarkers indicative for a productive human papillomavirus (HPV) infection (HPV E4) and a transforming HPV infection (p16ink4a, Ki‐67 and host‐cell DNA methylation) could provide guidance for clinical management i...

Background: In the Netherlands, the bivalent HPV vaccine (2vHPV) has been offered to preadolescent girls via the National Immunization Program (NIP) in a two-dose (2D) schedule since 2014. The current study estimates vaccine effectiveness (VE) against HPV infections up to four years post-vaccination among girls eligible for routine 2D immunization...