Johannes Berkhof

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

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...

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...

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: 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...

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 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 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...

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 prog...

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 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...

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...

Methylation of host‐cell DNA has been proposed as a promising biomarker for triage of high‐risk (hr) human papillomavirus (HPV) positive women at screening. This 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 in The Netherlands. Me...

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...

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...

Background Only clinically validated HPV assays can be accepted in cervical cancer screening. Objectives To update the list of high-risk HPV assays that fulfil the 2009 international validation criteria (Meijer-2009). Data Sources PubMed/Medline, Embase, Scopus, references from selected studies; published in January 2014-August 2020. Study eligi...

High‐grade cervical intraepithelial neoplasia (CIN2 and CIN3) represent 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...

Current clinical and histological classifications are unable to determine the risk of vulvar squamous cell carcinoma (VSCC) in high‐grade vulvar intraepithelial neoplasia (VIN), making prognostic biomarkers highly needed. We studied host‐cell DNA methylation markers in HSIL and dVIN without VSCC, in HSIL and dVIN adjacent to VSCC, and in human papi...

Background We aimed to derive an algorithm to define the optimal proportion of patients with mild cognitive impairment (MCI) in whom cerebrospinal fluid (CSF) testing is of added prognostic value. Methods MCI patients were selected from the Amsterdam Dementia Cohort ( n = 402). Three-year progression probabilities to dementia were predicted using...

Background: In human papillomavirus (HPV)-based cervical screening programs, management of HPV-positive women with normal cytology is debated. Longitudinal information on HPV type persistence may be employed for risk stratification. Methods: We assessed the risk of cervical intraepithelial grade 3 or worse (CIN3+) after repeatedly testing positi...

Background AMYPAD‐DPMS is the largest European, multicenter, prospective and randomized study assessing clinical utility and cost‐effectiveness of amyloid‐PET in a controlled but realistic clinical setting. In the present abstract we report preliminary results on the baseline features of the first study participants. Method A total of 900 particip...

Background It is unlikely that biomarker testing contributes to a more accurate prognosis in every patient with Mild Cognitive Impairment (MCI). We therefore aimed to derive a stepwise approach to select MCI patients for cerebrospinal fluid (CSF) testing and determine the optimal proportion of patients to receive CSF testing. Methods We selected n...

Background Human papillomavirus (HPV) vaccination programs achieve substantial population-level impact, with effects extending beyond protection of vaccinated individuals. We assessed trends in HPV prevalence up to eight years post-vaccination among men and women in the Netherlands, where bivalent HPV (2vHPV) vaccination, targeting HPV16/18, has be...

Multi-arm multi-stage clinical trials in which more than two drugs are simultaneously investigated provide gains over separate single- or two-arm trials. In this paper we propose a generic Bayesian adaptive decision-theoretic design for multi-arm multi-stage clinical trials with K ( K ≥ 2 ) arms. The basic idea is that after each stage a decision...

Background In many European countries, human papillomavirus (HPV) vaccine uptake among girls has remained below target levels, supporting the scope for vaccination of boys. We aimed to investigate if sex-neutral HPV vaccination can be considered cost-effective compared with girls-only vaccination at uptake levels equal to those among girls and unde...

In human papillomavirus (HPV) cervical cancer screening, cytology is used as triage to counter the low specificity of HPV testing. VALID‐SCREEN is a EU‐multicenter, retrospective study conducted to evaluate the clinical performance of the FAM19A4/miR124‐2 methylation‐based molecular triage test as a substitute or addition to cytology as reflex test...

Background: Despite advances in treatments, 30% to 50% of stage III-IV head and neck squamous cell carcinoma (HNSCC) patients relapse within 2 years after treatment. The Big Data to Decide (BD2Decide) project aimed to build a database for prognostic prediction modeling. Methods: Stage III-IV HNSCC patients with locoregionally advanced HNSCC trea...

Empirical evidence suggests that a fair proportion of dementia cases are preventable, that some preventive actions can be taken immediately, and others may soon be implemented. Primary prevention may target cognitively normal persons with modifiable risk factors through lifestyle and multiple domain interventions (including general cardiovascular h...

Background: For the prevention of chemotherapy-induced nausea and vomiting (CINV) during the delayed phase (24-120 hr) after moderately emetogenic chemotherapy (MEC), the use of 3-day dexamethasone (DEX) is often recommended. This study compared the efficacy and safety of two DEX-sparing regimens with 3-day DEX, focusing on delayed nausea. Patien...

Clinical criteria/Family history-based BRCA testing misses a large proportion of BRCA carriers who can benefit from screening/prevention. We estimate the cost-effectiveness of population-based BRCA testing in general population women across different countries/health systems. A Markov model comparing the lifetime costs and effects of BRCA1/BRCA2 te...

Birth cohorts vaccinated against human papillomavirus (HPV) are now entering cervical cancer screening. Assessment of (pre)cancer (CIN3+) risk is needed to assess the residual screening need in vaccinated women. We estimated the lifetime (screen‐detected) CIN3+ risk under five‐yearly primary HPV screening between age 30‐60, using HPV genotyping and...

The risk of vulvar squamous cell carcinoma (VSCC) in patients with high‐grade vulvar intraepithelial neoplasia (VIN) is considered lower in high‐grade squamous intraepithelial lesion (HSIL) compared to differentiated VIN (dVIN), but studies are limited. This study investigated both the incidence of high‐grade VIN and the cumulative incidence of VSC...

Objectives To evaluate the cross-sectional and long-term triage performance of FAM19A4/miR124-2 methylation analysis in human papillomavirus (HPV)-based cervical screening. Methods We conducted a post-hoc analysis within a Dutch population-based HPV-positive study cohort of women aged 30-60 years (n = 979). Cross-sectional CIN3+ sensitivity, speci...

Background & aims: A low muscle mass before start of treatment and loss of muscle mass during chemotherapy is related to adverse outcomes in patients with cancer. In this randomized controlled trial, the effect of nutritional counseling on change in muscle mass and treatment outcome in patients with metastatic colorectal cancer during first-line c...

Background Treatment of delirium often includes haloperidol. Second-generation antipsychotics like olanzapine have emerged as an alternative with possibly fewer side effects. The aim of this multicenter, phase III, randomized clinical trial was to compare the efficacy and tolerability of olanzapine with haloperidol for the treatment of delirium in...

Introduction/Background Vulvar intraepithelial neoplasia’s (VIN) comprise a heterogeneous disease entity and have an ambiguous vulvar squamous cancer (VSCC) risk. Human Papillomavirus (HPV) associated VIN accounts for more than 90% of all high-grade VIN, while HPV-induced vulvar squamous cell carcinomas (VSCC) only account for 25% of all VSCCs. Thi...

Introduction/Background High-grade vulvar intraepithelial neoplasia (VIN) is the precancerous state of vulvar squamous cell carcinoma (VSCC). Vulvar carcinogenesis is a heterogeneous disease with only a minority of VINs progressing to cancer. Because current clinical and histological classifications are insufficient to predict the cancer risk in wo...

Intense research activity in HPV modelling over this decade has prompted the development of additional guidelines to those for general modelling. A specific framework is required to address different policy questions and unique complexities of HPV modelling. HPV-FRAME is an initiative to develop a consensus statement and quality-based framework for...

Background: Biomarker-based risk predictions of dementia in people with mild cognitive impairment are highly relevant for care planning and to select patients for treatment when disease-modifying drugs become available. We aimed to establish robust prediction models of disease progression in people at risk of dementia. Methods: In this modelling...

Introduction: To construct a prognostic model based on amyloid positron emission tomography (PET) to predict clinical progression in individual patients with mild cognitive impairment (MCI). Methods: We included 411 MCI patients from the Alzheimer's Disease Neuroimaging Initiative. Prognostic models were constructed with Cox regression with demo...

Background: Compelling evidence links elevated levels of C-reactive protein (CRP) and other inflammatory markers to poor treatment outcome of antidepressant medication. Little is known about the contribution of low-grade inflammation to treatment response to electroconvulsive therapy (ECT) in severely depressed patients. Method: Associations bet...