Lone Kjeld Petersen

Pharmacokinetic comparison of cisplatin administration via HIPEC and intravenous infusion in a porcine model

The role of hyperthermia on abdominal tissue concentrations of cisplatin during and after intraperitoneal chemotherapy – insights from a porcine model

Epithelial ovarian cancer remains a leading cause of mortality among gynecological malignancies, with a high incidence of peritoneal carcinomatosis at diagnosis. Hyperthermic intraperitoneal chemotherapy (HIPEC) has emerged as a promising treatment for advanced-stage epithelial ovarian cancer, potentially improving recurrence-free and overall survival rates. The study aimed to investigate the impact of hyperthermia on cisplatin concentrations in healthy abdominal tissues by comparing HIPEC with normothermic intraperitoneal chemotherapy (NIPEC) in a novel porcine model. Sixteen cancer-free pigs underwent cytoreductive surgery followed by either HIPEC or NIPEC, with cisplatin administered intraperitoneally. Microdialysis was used to measure local cisplatin concentrations in various abdominal tissues over a 6-h period. The analysis revealed no statistically significant or clinically relevant difference in cisplatin concentrations between the HIPEC and NIPEC groups. In both groups, cisplatin concentrations were consistently higher in the peritoneum than in other tissues, and plasma levels were significantly lower than those in abdominal tissues. Hyperthermia did not enhance cisplatin's tissue penetration, suggesting that NIPEC may be an effective alternative to HIPEC, particularly for fragile and elderly patients. Future studies should investigate whether hyperthermia improves cisplatin delivery and cytotoxicity in tumor-infiltrated peritoneal tissues.

Improving diagnostic of cervical dysplasia among postmenopausal women aged ≥50 years using local vaginal oestrogen treatment prior to colposcopy: study protocol for a multicentre randomised controlled trial (the IDEAL study)

Introduction Colposcopy is the most important diagnostic tool to detect cervical precancerous lesions and thereby prevention of cervical cancer. Due to age-dependent changes of the cervix, colposcopy is challenging in postmenopausal women, as the majority will have a non-visible transformation zone, resulting in increased risk of missing disease, a diagnostic cone biopsy and prolonged follow-up with repeated colposcopies. This study will be among the first to investigate, if treatment with vaginal oestrogen prior to colposcopy will improve the colposcopy performance, to ensure accurate and timely diagnosis of precancerous cervical lesions among postmenopausal women. Methods and analysis A randomised blinded controlled multicentre study. Enrolment will be performed at gynaecology departments in Central Denmark Region and Region of Southern Denmark. A total of 150 postmenopausal women aged ≥50 years referred for colposcopy due to abnormal cervical screening results will be randomised 1:1 to either pretreatment with vaginal application of Vagifem 30 µg or placebo once a day for 14 days prior to colposcopy. The primary outcome will be to compare the percentage of women in the two groups with a visible transformation zone at colposcopy, and biopsies representative of the transformation zone. Secondary outcomes will be the proportion of detected cervical intraepithelial neoplasia grade 2 or higher in the cervical biopsies; the proportion of diagnostics cone biopsies; the patients’ report on possible side effects and compliance to the pretreatment. Ethics and dissemination The study has been approved by the Central Denmark Region Committee on Biomedical Research Ethics (1-10-72-34-22), the Central Denmark Regions’ Research Unit (1-16-02-72-22) and The Danish Health Authority (Danish Medicine Agency; 2022015030). The study’s EudraCT number is (1-23-456; 2022-000269-42) and it is registered on www.clinicaltrials.gov . The local Good Clinical Practice (GCP) unit will supervise and monitor the study closely before, during and after the study period. Findings will be disseminated in peer-reviewed scientific journals and presented in relevant conferences. Trial registration number NCT05283421 .

Adherence to follow‐up after the exit cervical cancer screening test at age 60–64: A nationwide register‐based study

AbstractBackgroundIn Denmark, human papillomavirus (HPV) testing has replaced cytology in primary cervical cancer screening for women aged 60–64; at this age, women are invited for the last (exit) screening test within the national organized program.AimWe investigated the adherence of these women to the recommended follow‐up after a non‐negative (positive or inadequate) HPV test and the overall resource use during that follow‐up.Materials & MethodsWe included all 2926 women aged 60–64 years with nonnegative HPV screening tests between March 2012 and December 2016. All relevant follow‐up tests and procedures were retrieved until the end of 2020 from the highly complete Danish administrative health registers, and the data were linked at the individual level. We determined the extent to which the adherence patterns followed the national recommendations for follow‐up and estimated the total numbers of tests and diagnostic procedures utilized during the entire process.ResultsIn total, only 26% of women had follow‐up in accordance with the recommendations; 4% had no follow‐up, 46% had insufficient follow‐up, and 24% had more follow‐up than recommended. We estimated that 17% of women remained in follow‐up for longer than 4 years. The average numbers of diagnostic tests and procedures used after positive HPV screening were higher than expected, even among women who had insufficient follow‐up, that is, those who received less invasive procedures than recommended, or experienced delays in receiving those procedures.ConclusionTo conclude, we found that the patterns of follow‐up of women with nonnegative primary HPV screening tests at 60–64 often diverged from the recommendations. Addressing these inconsistencies in follow‐up by providing evidence for optimal clinical management should help improve the quality of screening programs and secure an equal and reliable follow‐up care service for all women.

Performance of HPV E4 and p16 INK4a biomarkers in predicting regression of cervical intraepithelial neoplasia grade 2 (CIN2): protocol for a historical cohort study

Introduction Cervical intraepithelial neoplasia grade 2 (CIN2) represents a spectrum of lesions with variable progression and regression. Pathological diagnosis of CIN2 is subjective and poorly reproducible. Accurate diagnosis and identification of different patterns of CIN2 related to outcome are essential to reduce the risks of overtreatment or undertreatment. It is important to explore novel methods for risk stratification of CIN2 to enable targeted treatment of women at high risk of progression or persistent disease and follow-up of women at low risk. The combination of the novel biomarker human papillomavirus (HPV) E4 with p16 INK4a targets steps in the transition from a productive oncogenic HPV infection (CIN1) to a transformed lesion (CIN3) within CIN2. Previous cross-sectional studies suggest that HPV E4 combined with p16 INK4a may be valuable for risk assessment of CIN2. However, data on HPV E4/p16 INK4a as a predictor for CIN2 regression is lacking. Methods and analysis We will conduct a historical cohort study including 500 women aged 23–40 years with a first CIN2 diagnosis in Aarhus, Denmark during 2000–2010. Women will be eligible if they have undergone active surveillance and have no previous record of hysterectomy, cone biopsy, and CIN2 or worse. Women will be randomly selected through the Danish Pathology Databank. Tissue samples from women included will be sectioned for p16 INK4a and HPV E4 immunohistochemical staining in addition to conventional hematoxylin and eosin (H&E) staining. A positive result will be defined as HPV E4 positive. Through the Danish Pathology Databank, we will collect results on all subsequent cervical biopsies. Regression will be used as the primary outcome. Ethics and dissemination The study has been approved by the Ethical Committee in Central Denmark Region (1-10-72-60-20) and registered at the Faculty of Health, Aarhus University. Results will be published in a peer-reviewed journal and presented at scientific meetings. Trial registration number NCT05049252 .

An explainable attention model for cervical precancer risk classification using colposcopic images

Cervical cancer remains a major worldwide health issue, with high morbidity and mortality rates if diagnosed and treated at a later stage. Early identification and risk assessment are crucial for preventive interventions. This paper presents the Cervix-AID-Net model for classifying cervical precancer risk using still images captured from a DYSIS colposcope. The study designs and evaluates the proposed Cervix-AID-Net model to classify high-risk and low-risk cervical precancer classes. The model comprises a Convolutional Block Attention Module (CBAM) and convolutional layers that extract interpretable and representative features from colposcopic images to distinguish high-risk and low-risk cervical precancer. In addition, the proposed Cervix-AID-Net model integrates gradient class activation maps, Local Interpretable Model-agnostic Explanations, CartoonX, and pixel rate distortion techniques to explain model decisions using output feature maps and input features. The evaluation using holdout and ten-fold cross-validation techniques yielded classification accuracies of 99.33% and 99.81%, respectively. The analysis revealed that CartoonX provides meticulous explanations for the decision of the Cervix-AID-Net model due to its ability to provide the relevant piecewise smooth part of the image. The effect of Gaussian noise and blur on the input shows that the performance remains unchanged up to Gaussian noise of 3% and blur of 10%, while the performance decreases thereafter. A comparison study of the proposed model's performance with other deep learning approaches highlights the Cervix-AID-Net model's potential as a supplemental tool for increasing the effectiveness of cervical precancer risk assessment. The proposed method, which incorporates CBAM and explainable artificial intelligence, has the potential to influence the prevention and early detection of cervical cancer. Thus, the proposed framework will help improve patient outcomes and reduce the worldwide burden of this preventable disease.

Improving Diagnostics in Cervical Dysplasia

Cervical cancer is the fourth most common cancer in women worldwide. It is caused by an infection with human papillomavirus (HPV). A persistent infection with HPV is associated with increased risk of precancerous lesions, which may further develop into cervical cancer. To reduce the disease burden, accurate and timely diagnosis of cervical precancerous lesions are crucial. To identify cervical precancerous lesions, women are referred to colposcopy, which is the most important diagnostic tools to detect cervical precancerous lesions. It allows close visualization of the cervix in order to collect biopsies in the area called transformation zone (TZ), which is where precancerous lesions develop. It is essential for the physician to identify the TZ during colposcopy in order to obtain correct diagnosis. For women aged ≥50 this is often a challenge as TZ naturally with age, will retract further into the cervical canal, making the area for sampling invisible, and thereby the colposcopy inadequate. Consequently, this increases the risk of developing cancer due to diagnostic delay, and the risk of several colposcopy examinations or overtreatment (cone biopsy), before a final diagnosis is achieved. Few studies suggest that pretreatment with local vaginal estrogen prior to colposcopy may improve visualization of the TZ. Thereby, obtaining more accurate biopsies from the cervix, and thus making a more accurate and timely diagnosis in the first outpatient visit. The primary purpose of this study is to evaluate pre-diagnostic treatment with estrogen to improve the diagnosis of women with cervical precancerous lesions, in order to prevent cervical cancer. The study ia s randomized controlled double-blind multicenter study. The investigators will use information from Danish National Patient registry, and data from the Danish Pathology Data Bank. Enrollment will take place at the Departments of Gynecology in Denmark. Eligible women aged ≥ 50 years will be randomized 1:1 to receive local vaginal estrogen or placebo prior to the colposcopic examination. The investigators believe the results will provide the prerequisite for obtaining correct diagnosis, and thereby provide basis for choosing the right individualized examination- and treatment plan. The results will also contribute with important knowledge, that may help reduce the incidence and mortality rate of cervical cancer.