Papers by Bart Hellebrekers
Human Reproduction, Jun 1, 2000
Purpose: Therapeutic vaccination with human papillomavirus type 16 (HPV16) E6 and E7 synthetic lo... more Purpose: Therapeutic vaccination with human papillomavirus type 16 (HPV16) E6 and E7 synthetic long peptides (SLP) is effective against HPV16-induced high-grade vulvar and vaginal intraepithelial neoplasia (VIN/VaIN). However, clinical nonresponders displayed weak CD8+ T-cell reactivity. Here, we studied if imiquimod applied at the vaccine site could improve CD8+ T-cell reactivity, clinical efficacy, and safety of HPV16-SLP (ISA101).Experimental Design: A multicenter open-label, randomized controlled trial was conducted in patients with HPV16+ high-grade VIN/VaIN. Patients received ISA101 vaccination with or without application of 5% imiquimod at the vaccine site. The primary objective was the induction of a directly ex vivo detectable HPV16-specific CD8+ T-cell response. The secondary objectives were clinical responses (lesion size, histology, and virology) and their relation with the strength of vaccination-induced immune responses.Results: Forty-three patients were assigned to ei...
supplementary material and methods Table S1. Reasons for exclusion of patients from outcome analy... more supplementary material and methods Table S1. Reasons for exclusion of patients from outcome analysis Table S2. Summary statistics of patient groups according to linear mixed model analysis Table S3. All related systemic adverse events by study group Table S4. Swelling size of injection site at 12 months follow-up (safety population) Table S5. Overview of treatment-related severe adverse events in patients who received at least one ISA101 vaccination with or without imiquimod Table S6. Overview of serious adverse events (safety population) Figure S1. Study Profile Figure S2. Example of detection of HPV16-specific CD8+ T-cell response measured by flow cytometry Figure S3. Example of detection of HPV16-specific CD8+ T-cell response measured by ex-vivo CD8+ T-cell IFNγ-ELISPOT Figure S4. HPV16-specific CD8+ T-cell reactivity of the PP population Figure S5. No differences in immune response to recall antigens upon treatment Figure S6. Strength of the HPV16-specific immunity versus clini...
Gynecological Surgery, 2013
The exact incidence of scar endometriosis is unknown. The aim of this study is to determine the i... more The exact incidence of scar endometriosis is unknown. The aim of this study is to determine the incidence of endometriosis in the abdominal wall following a caesarean section. Women who underwent surgery for scar endometriosis after a caesarean section and the total number of women with caesarean sections in The Haga Teaching Hospital, a gynaecologic centre in The Netherlands, were identified by the national obstetric registration and pathology archive in the period January 1995 to December 2008. Clinical data were collected from the existing hospital records. Twenty-nine women were diagnosed with scar endometriosis after a caesarean section, and 3,047 women underwent one or more caesarean sections, resulting in an incidence of scar endometriosis of 0.95 %. None of the women had a history of endometriosis. Symptoms were pain (94.0 %), cyclic with menstruation (50.0 %) and swelling of the scar (89.0 %). Mean time between caesarean delivery and symptoms was 4.1 years. No recurrence occurred. This study reveals a higher incidence of endometriosis in the scar of a caesarean section than described in current literature. To improve the detection rate, more attention to medical history and physical examination is mandatory. A higher incidence warrants research into the pathophysiology and prevention of endometriosis in the scar of a caesarean section.
International Journal of Cancer, 2020
Immunotherapy of vulvar high‐grade squamous intraepithelial lesion (vHSIL) is investigated as an ... more Immunotherapy of vulvar high‐grade squamous intraepithelial lesion (vHSIL) is investigated as an alternative for surgery, because of high comorbidity and risk of recurrence. Limited evidence exists on the role and composition of the immune microenvironment in current immunotherapeutic approaches for vHSIL. The vHSIL of 29 patients biopsied before treatment with imiquimod were analyzed by two multiplex seven‐color immunofluorescence panels to investigate the pre‐existing T‐cell and myeloid cell composition in relation to treatment response. The samples were scanned with the Vectra multispectral imaging system. Cells were automatically phenotyped and counted with inForm advanced image analysis software. Cell counts and composition were compared to that of vHSIL patients before therapeutic vaccination (n = 29) and to healthy vulva (n = 27). Our data show that the immune microenvironment of complete responders (CR) to imiquimod resembled the coordinated infiltration with type 1 CD4+ and CD8+ T cells and CD14+ inflammatory myeloid cells also found in healthy vulva. However, more CD8+ T cells and FoxP3+ regulatory T cells were present in CR. The lesions of partial responders (PR) lacked such a coordinated response and displayed an impaired influx of CD14+ inflammatory myeloid cells. Importantly, complete responses after imiquimod or therapeutic vaccination showed the same dependency on a pre‐existing coordinated type 1 T‐cell and CD14+ myeloid cell infiltration. In conclusion, a good clinical outcome after two different forms of immunotherapy for vHSIL is associated with the presence of a primary inflammatory process resulting in the coordinated influx of several types of immune cells which is then amplified.
Thrombosis and Haemostasis, 2000
SummaryFibrin deposition, the primary step in the formation of post-surgical adhesions, is the re... more SummaryFibrin deposition, the primary step in the formation of post-surgical adhesions, is the result of a disbalance between the fibrinforming and the fibrin-dissolving capacity of the peritoneum. Literature data suggest a transient reduction in local plasminogen activator activity after peritoneal trauma, which results in a reduction of fibrinolysis and permits deposited fibrin to become organized into fibrous, permanent adhesions. In the present study, the fibrinolytic parameters tissue-type plasminogen activator (tPA; antigen and activity) and plasminogen activator inhibitor type-1 (PAI-1; antigen and activity) were measured in peritoneal fluid, in peritoneal biopsies and in plasma to establish the time course of changes in fibrinolytic activity.A standardized peritoneal adhesion model in the rat.Analysis, over a 72-h period following surgical trauma, of the main fibrinolytic parameters in peritoneal lavage, in biopsies of damaged and undamaged peritoneum, and in plasma, and det...
International Journal of Gynecological Cancer, 1999
The objectives of this study were to scrutinize surgical features and analyze local tumor paramet... more The objectives of this study were to scrutinize surgical features and analyze local tumor parameters of early cervical cancer to identify patients at-risk for recurrent disease. Three hundred eight patients who underwent radical hysterectomy and pelvic lymphadenectomy between 1984 and 1997 were studied retrospectively. All radical hysterectomies were performed in a referral oncology center, and treatment policies and operating staff were the same during the study period. Operating time gradually decreased significantly during the study period from an average of 270 min to an average of 187 min (P < 0.0001), and blood loss during surgery also decreased continually from 1515 ml to 1071 ml (P < 0.0001). Postoperative radiation treatment was given to 119 patients (40%). The overall five-year survival rate was 83%, 91% for those with negative, and 53% for those with positive pelvic nodes. Univariate analysis showed that lymph node status, parametrial involvement, status of the surgical margins, capillary lymphatic space involvement, tumor size and depth of invasion were all significantly related to the occurrence of recurrent disease. Multivariate analysis revealed that lymph node involvement (hazard ratio 4.4), parametrial involvement, tumor size and depth of invasion were independent factors of prognostic significance for disease-free survival. It was concluded that the local control of cervical tumors infiltrating > 10 mm (hazard ratio 5.1) might be improved by adjuvant radiotherapy, even in the absence of lymph node metastasis, parametrial involvement or affected surgical margins.
International Journal of Cancer, 2014
Immunotherapy of usual vulvar intraepithelial neoplasia (uVIN) is promising; however, many patien... more Immunotherapy of usual vulvar intraepithelial neoplasia (uVIN) is promising; however, many patients still fail to show clinical responses, which could be explained by an immune escape through alterations in human leukocyte antigen (HLA) expression. Therefore, we analyzed a cohort of patients with a primary (n 5 43) and subsequent recurrent uVIN lesion (n 5 20), vaccinetreated uVIN patients (n 5 12), patients with human papillomavirus (HPV)-induced vulvar carcinoma (n 5 21) and healthy controls (n 5 26) for the expression of classical HLA-class I/II and nonclassical HLA-E/-G and MHC class I chain-related molecule A (MICA). HLA-class I was downregulated in 70% of uVIN patients, including patients with a clinical response to immunotherapy. Downregulation of HLA-class I is probably reversible, as only 15% of the uVIN cases displayed loss of heterozygosity (LOH) and HLA-class I could be upregulated in uVIN keratinocyte cultures by interferon c. HLA-class I downregulation is more frequently associated with LOH in vulvar carcinomas (25-55.5%). HLA-class II was found to be focally expressed in 65% of uVIN patients. Of the nonclassical molecules, MICA was downregulated in 80% of uVIN whereas HLA-E and-G were expressed in a minority of cases. Their expression was more prominent in vulvar carcinoma. No differences were found between the alterations observed in paired primary and recurrent uVIN. Importantly, downregulation of HLA-B/C in primary uVIN lesions was associated with the development of recurrences and progression to cancer. We conclude that downregulation of HLA is frequently observed in premalignant HPV-induced lesions, including clinical responders to immunotherapy, and is associated with worse clinical outcome. However, in the majority of cases downregulation may still be reversible. Usual vulvar intraepithelial neoplasia (uVIN) is a chronic premalignant skin condition with an increasing incidence mainly in young women, which is caused by a persistent high-risk human papillomavirus (HPV) infection in more than 90% of cases. 1,2 uVIN causes complaints of severe and long-lasting pruritis, pain and sexual dysfunction and has a malignant potential of 3-4% in treated and of 9% in untreated patients. 1,3 Because conventional treatments for uVIN are characterized by high recurrence rates of 20-40% and psychosexual problems, there is a need for alternative therapies. 4-6 Failure of the immune system to induce a strong and effective immune response to HPV is known to cause
Clinical Cancer Research, 2008
Purpose: To characterize HPV16 E6- and E7-specific T-cell immunity in patients with high-grade sq... more Purpose: To characterize HPV16 E6- and E7-specific T-cell immunity in patients with high-grade squamous intraepithelial lesions (HSIL). Experimental Design: Peripheral blood mononuclear cells isolated from 38 patients with HPV16+ HSIL were used to determine the magnitude, breadth, and polarization of HPV16-specific T-cell responses by proliferation assays and cytokine assays. Furthermore, HSIL-infiltrating T cells isolated from 7 cases were analyzed for the presence of HPV16 E6- and/or E7-specific T cells, phenotyped, and tested for the specific production of IFN-γ and interleukin-10 as well as for their capacity to suppress immune responses. Results: HPV16-specific T-cell responses were absent in the circulation of the majority (∼60%) of patients who visit the clinic for treatment of a HPV16+ HSIL lesion. Notably, HPV16-specific T-cell reactivity was predominantly detected in patients returning to the clinic for repetitive treatment of a persistent or recurrent HPV16+ HSIL lesion a...
Case Reports in Perinatal Medicine, 2015
Amniotic bands are believed to be formed as a result of chorio-amniotic membrane separation, whic... more Amniotic bands are believed to be formed as a result of chorio-amniotic membrane separation, which produces free-floating tissue bands. These amniotic bands can cause a wide range of clinical abnormalities, known as amniotic band syndrome. Amniotic bands can also be swallowed by the fetus, thus causing, for instance, facial clefting. However, few studies have reported swallowing of amniotic bands. Thus, we report a case of a term infant who was born with a large ingested amniotic band hanging from the mouth.
American journal of obstetrics and gynecology, 2021
BACKGROUND Obstetrics and gynecology requires complex decision-making and skills due to unexpecte... more BACKGROUND Obstetrics and gynecology requires complex decision-making and skills due to unexpected high-risk situations. These skills are influenced by alertness, reaction time and concentration. Night shifts result in sleep deprivation, which might impair these functions, although it is still unclear to what extent. OBJECTIVE The aim of this study was to investigate whether a night shift routinely impairs the Obstetrics or Gynecology consultants' and residents' fitness to perform (FTOP) and whether this reaches a critical limit as compared to relevant frames of reference. STUDY DESIGN Residents (n=33) and consultants (n=46) in obstetrics and gynecology conducted multiple measurements at precall, postcall and non-call moments with the FTOP self-test. The self-test consists of a s-eye coordination task that is able to objectively measure alertness, reaction time, concentration and hand-eye coordination, and visual analogue scales to subjectively score alertness. The test is v...
Results The surgical procedure and indication for treatment remained unchanged during the study p... more Results The surgical procedure and indication for treatment remained unchanged during the study period. This applied also to the surgical team. The women’s age increased significantly during the study years, as was the case with the number of nodes removed. The depth of infiltration by the tumour increased steadily throughout the study, but this failed to reach statistical significance. The distribution of FIG0 stages, percentage of positive lymph nodes, radicality of the surgical margins and post-operative morbidity remained the same. Overall, the five year survival rate was 83%; for women with negative nodes 91%, and for women with positive nodes 53%. Survival tended to improve during the course of the study, but this was not statistically significant. Blood loss during surgery decreased consistently during the whole study period, from a mean of 1515 mL at the beginning of the study to a mean of 1071 mL at the end (P < 0-OOOl). The operating time also diminished significantly b...
BJOG: An International Journal of Obstetrics and Gynaecology, 2000
Objective To study the development of surgical performance of an unchanging surgical team over 13... more Objective To study the development of surgical performance of an unchanging surgical team over 13 years. Design Prospective, observational study. Setting A university hospital, The Netherlands. Participants Three hundred and eight women who underwent surgical treatment for early cervical cancer.
Acta Obstetricia et Gynecologica Scandinavica, 2000
Human Reproduction, 2011
background: Misoprostol is an agent that may ripen the cervix in nonpregnant women. Here, we inve... more background: Misoprostol is an agent that may ripen the cervix in nonpregnant women. Here, we investigate whether vaginal misoprostol administered prior to intrauterine device (IUD) insertion reduces the number of failed insertions, insertion-related complications and pain during insertion. methods: We conducted a double-blinded, multicenter randomized controlled trial among patients requesting an IUD. Nulli-and multi-parous women were included, and both copper-containing and levonorgestrel-releasing IUDs were used. Participants were allocated to either 400 mg misoprostol or placebo (administered 3 h prior to IUD insertion). The primary outcome measure was failed insertion. Secondary outcome measures were insertion-related complications, pain, difficulty of insertion and side-effects. results: Two hundred and seventy participants were randomized. After drop out for various reasons (mainly no show), 199 participants had an IUD inserted; 102 received misoprostol and 97 received placebo. Only three insertions failed; two in the misoprostol group and one in the placebo group [P ¼ 0.59, relative risk (RR) 1.9, 95% confidence interval (CI) 0.2-20.6]. The overall incidence of insertion-related complications was 21.8% in the misoprostol versus 19.1% in the placebo group (mainly vasovagal-like reactions) and did not differ between groups (P ¼ 0.65, RR 1.1, 95% CI 0.7-2.0). No difference in pain scores between groups was found. Side-effects were more common in the misoprostol group (P ¼ 0.05, RR 1.3, 95% CI 1.0 -1.7).
Surgical Endoscopy, 2009
Postoperative adhesions remain an important clinical problem, accounting for infertility, chronic... more Postoperative adhesions remain an important clinical problem, accounting for infertility, chronic pain and bowel obstruction. Its prevention is still inadequate and overall poorly understood. The aim of this study was to investigate the effect of Reteplase (a recombinant plasminogen activator, r-PA) and of PAI-1 antibodies upon adhesion formation in a laparoscopic model. Pneumoperitoneum-enhanced adhesions were induced by performing a bipolar lesion in female BALB/c mice and by using pure and humidified CO(2) as insufflation gas for 60 min. In experiment 1, four doses of 0.125, 0.25, 0.5 and 1 mg/0.5 ml r-PA and one and two doses of 1 mg r-PA were administrated i.p. Two control groups were included, one without any treatment and the second one receiving four times 0.5 ml of saline. In experiment 2, four doses of 0, 1, 10 and 100 microg/0.5 ml r-PA were administrated i.p. In experiment 3, PAI-1 neutralising and non-neutralising antibodies were injected i.p. after performing the lesion on day 0 and days 2 and 4. Adhesions were scored after 7 days. Adhesion formation was less with the administration of four doses of 1 microg r-PA (proportion, p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.04, Wilcoxon). An increase in adhesion formation was observed when higher number of doses and amounts of r-PA were used (Proc GLM, eight groups, two variables, p = 0.05 for the amount of r-PA and p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.02 for the number of doses administrated). No effect was observed with the PAI-1 antibodies. Low-dose i.p. administration of rPA is effective in the prevention of adhesions in a laparoscopic mouse model.
Clinical cancer research : an official journal of the American Association for Cancer Research, Jan 26, 2016
Therapeutic vaccination with human papillomavirus type 16 (HPV16) E6 and E7 synthetic long peptid... more Therapeutic vaccination with human papillomavirus type 16 (HPV16) E6 and E7 synthetic long peptides (SLP) is effective against HPV16-induced high-grade vulvar and vaginal intraepithelial neoplasia (VIN/VaIN). However, clinical non-responders displayed weak CD8+ T-cell reactivity. Here, we studied if imiquimod applied at the vaccine site could improve CD8+ T-cell reactivity, clinical efficacy and safety of HPV16-SLP (ISA101). A multicentre open-label, randomised controlled trial was conducted in patients with HPV16+ high-grade VIN/VaIN. Patients received ISA101 vaccination with or without application of 5% imiquimod at the vaccine site. The primary objective was the induction of a directly ex-vivo detectable HPV16-specific CD8+ T-cell response. The secondary objectives were clinical responses (lesion size, histology and virology) and their relation with the strength of vaccination-induced immune responses. Forty-three patients were assigned to either ISA101 with imiquimod (n=21) or I...
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Papers by Bart Hellebrekers