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Simple Summary In this exploratory study, we aimed to compare biomarker profiles in patients with multiple high-risk human papillomavirus (HPV)-associated vulvar precursor lesions, which is called multifocal high-grade squamous intraepithelial lesion (HSIL). The HPV-positive HSILs were tested for HPV genotype, expression of two immunohistochemical markers p16INK4a and Ki-67, and DNA methylation of six genes. Generally, the biomarkers showed similar expression between lesions. Occasionally, marked differences were observed, indicating that not all multifocal lesions are the same. Our study contributes to a better understanding of the value of potential diagnostic, prognostic, and predictive biomarkers in patients with vulvar multifocal HSIL. Validation in larger cohorts will be important. Abstract In patients with high-grade squamous intraepithelial lesion (HSIL) of the vulva, the presence of multiple lesions, called multifocal HSIL, is common. The aim of this exploratory study was to investigate biomarker expression profiles in multifocal HSIL. In total, 27 lesions from 12 patients with high-risk human papillomavirus (HPV)-positive multifocal HSIL were tested for HPV genotype, expression of p16INK4a and Ki-67, and DNA methylation of six genes. HPV16 was found most commonly in 21 (77.8%) HSILs. In two (16.4%) patients, HPV genotype differed between the lesions. All lesions demonstrated diffuse p16INK4a staining, of which three (11.1%) were combined with patchy staining. One patient (8.3%) demonstrated markedly different DNA methylation levels between lesions. Generally, heterogeneity in methylation profiles was observed between different patients, even when other biomarkers showed similar expression. In conclusion, this study is the first to demonstrate heterogeneity of individual lesions in patients with multifocal HSIL. The studied biomarkers have the potential to refine prognostic and predictive diagnostics. Future prospective, longitudinal studies are needed to further explore the potential of a biomarker profile for management of patients with multifocal HSIL.

Objectives. The challenge when performing cytoreductive surgery (CRS) is to balance the benefits and risks. The aim of this study was to report short term postoperative morbidity and mortality in relation to surgical outcome in patients undergoing primary debulking surgery (PDS) or interval debulking (IDS) surgery in the Netherlands. Methods. The Dutch Gynecological Oncology Audit (DGOA) was used for retrospective analysis. Patients undergoing PDS or IDS between January 1st, 2015 -December 31st, 2018 were included. Outcome was frequency of postoperative complications. Median time to adjuvant chemotherapy and severity of complications were related to outcome of CRS. Complications with Clavien-Dindo >= 3 were analyzed per region and case mix corrected. Statistical analysis was performed with R.Studio. Results. 1027 patients with PDS and 1355 patients with IDS were included. Complications with re-invention were significantly higher in PDS compared to IDS (5.7% vs. 3.6%, p = 0.048). Complete cytoreduction was 69.7% in PDS and 62.1% IDS, p < 0.001. Time to adjuvant chemotherapy was 49 days in patients with complete CRS and a complication with re-intervention. Regional variation for severe complications showed one region outside confidence intervals. Conclusions. Higher complete cytoreduction rate in the PDS group indicates that the correct patients have been selected, but is associated with a higher percentage of complication with re-intervention. As result, time to start adjuvant chemotherapy is longer in this group. Maintaining a balance in aggressiveness of surgery and outcome of the surgical procedure with respect to severe complications is underlined. Bench marked data should be discussed nationally to improve this balance. (c) 2021 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http:// creativecommons.org/licenses/by/4.0/).

Dear Editor, We would like to comment on the paper 'Prognostic factors in patients with vulvar cancer: the VULCAN study' by Zapardiel et al.[1][1] We have many concerns. For example, reference 3 refers to patients with vulvar intra-epithelial neoplasia, not invasive vulvar cancer. The latter is not

Abstract Purpose Purpose is to: (1) study effectiveness of the hospital-based work support intervention for cancer patients at two years of follow-up compared to usual care and (2) identify which early factors predict time to return-to-work (RTW). Methods In this multi-center randomised controlled trial (RCT), 106 (self-)employed cancer patients were randomized to an intervention group or control group and provided 2 years of follow-up data. The intervention group received patient education and work-related support at the hospital. Primary outcome was RTW (rate and time) and quality of life (SF-36), and secondary outcomes were, work ability (WAI), and work functioning (WLQ). Univariate Cox regression analyses were performed to study which early factors predict time to full RTW. Results Participants were diagnosed with breast (61%), gynaecological cancer (35%), or other type of cancer (4%). RTW rates were 84% and 90% for intervention versus control group. They were high compared to national register-based studies. No differences between groups were found on any of the outcomes. Receiving chemotherapy (HR = 2.43, 95% CI 1.59–3.73 p Conclusions We found high RTW rates compared to national register-based studies and we found no differences between groups. Future studies should therefore focus on reaching the group at risk, which consist of patients who receive chemotherapy, have a low level of education and have a low work ability at diagnosis. Trial registration Netherlands Trial Registry (NTR) (http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=1658): NTR1658.

BackgroundThe efficacy of adjuvant radiotherapy in patients with intermediate risk early cervical cancer after radical hysterectomy is still under debate. Most guidelines recommend adjuvant radiotherapy, whereas others consider observation a viable option.ObjectiveTo investigate if patients with intermediate risk factors for cervical cancer who underwent radical hysterectomy may benefit from adjuvant radiotherapy.MethodsConsecutive patients with tumor confined to the cervix and intermediate risk factors (according to Sedlis), treated between January 1982 and December 2014 who were observed after a type C2 radical hysterectomy formed the basis for this study. The frequency of recurrences, specifically isolated loco-regional recurrences, and the risk of death from recurrences, were analyzed. Data were analyzed using SPSS, version 23.0 for WindowsResultsA total of 161 patients were included in the analysis. Median age was 40 (range 20–76). Stages IB1 and IB2 were seen in 87 (54%) and 74 patients (46%), respectively. Squamous cell and non-squamous histology was seen in 114 (70.8%) and 47 patients (29.2%), respectively. Of the 161 patients, 25 (15.5%) had recurrent disease, of whom nine had an isolated loco-regional recurrence (5.6%). Median time to recurrence for isolated loco-regional recurrences was 28 months (range 9–151). Treatment for an isolated loco-regional recurrence was radiotherapy (n = 4) and chemoradiotherapy (n = 5). Four patients (2.5%) died from disease as a result of an isolated loco-regional recurrence. Actuarial disease- specific survival was 93.0% for the total group. No variables were found that predicted an isolated loco-regional recurrence.DiscussionThe mortality from isolated loco-regional recurrence in patients with intermediate risk factors for cervical cancer who underwent only radical hysterectomy type C2 was 2.5%. Further studies should compare outcomes between patients who undergo a type C2 radical hysterectomy without adjuvant radiotherapy with those undergoing a less radical hysterectomy but with adjuvant radiotherapy.

Purpose To investigate whether initial diagnostic laparoscopy can prevent futile primary cytoreductive surgery (PCS) by identifying patients with advanced-stage ovarian cancer in whom > 1 cm of residual disease will be left after PCS. Patients and Methods This multicenter, randomized controlled trial was undertaken within eight gynecologic cancer centers in the Netherlands. Patients with suspected advanced-stage ovarian cancer who qualified for PCS were eligible. Participating patients were randomly assigned to either laparoscopy or PCS. Laparoscopy was used to guide selection of primary treatment: either primary surgery or neoadjuvant chemotherapy followed by interval surgery. The primary outcome was futile laparotomy, defined as a PCS with residual disease of > 1 cm. Primary analyses were performed according to the intention-to-treat principle. Results Between May 2011 and February 2015, 201 participants were included, of whom 102 were assigned to diagnostic laparoscopy and 99 to primary surgery. In the laparoscopy group, 63 (62%) of 102 patients underwent PCS versus 93 (94%) of 99 patients in the primary surgery group. Futile laparotomy occurred in 10 (10%) of 102 patients in the laparoscopy group versus 39 (39%) of 99 patients in the primary surgery group (relative risk, 0.25; 95% CI, 0.13 to 0.47; P < .001). In the laparoscopy group, three (3%) of 102 patients underwent both primary and interval surgery compared with 28 (28%) of 99 patients in the primary surgery group ( P < .001). Conclusion Diagnostic laparoscopy reduced the number of futile laparotomies in patients with suspected advanced-stage ovarian cancer. In women with a plan for PCS, these data suggest that performance of diagnostic laparoscopy first is reasonable and that if cytoreduction to < 1 cm of residual disease seems feasible, to proceed with PCS.

Background: Vulvar Paget disease (VPD) is a rare skin disorder that is considered premalignant.Objective: To assess the clinical course, treatment schedules, and effect of invasion and treatment on recurrence and survival in patients with VPD.Methods: Data on women with VPD were retrieved from the medical files and pathology reports in all Dutch tertiary university medical centers. Disease-free survival and 5-year disease-specific survival were estimated by using Kaplan-Meier curves.Results: Data on 113 patients whose VPD was diagnosed between 1991 and 2016 were analyzed; 77% had noninvasive VPD. Most of the women (65%) underwent a surgical procedure. Recurrences were reported in 40%. Of the women with noninvasive VPD, 8% developed invasion. There were no disease-specific deaths reported in the women with noninvasive VPD. The 5-year disease-specific survival rate was greater than 98% in noninvasive and microinvasive VPD, but significantly worse in invasive VPD (50% [P Limitations: The main limitations of this study are its retrospective character and the fact that original pathology samples were not available for reassessment.Conclusions: VPD is extremely rare, and the recurrence rates are high. Most patients have noninvasive VPD, which does not affect survival and should be considered a chronic disorder with limited invasive potential. In cases of invasive disease, survival decreases significantly.

Introduction: The care for patients with epithelial ovarian cancer(EOC) is organised in eight different geographical regions in the Netherlands. This situation allows us to study differences in practice patterns and outcomes between geographical regions for patients with FIGO stage IIIC and IV.Methods: We identified all EOC patients who were diagnosed with FIGO stage IIIC or IV between 01.01.2008 and 31.12.2015 from the Netherlands Cancer Registry. Descriptive statistics were used to summarize treatment and treatment sequence(primary cytoreductive surgery(PCS) or neoadjuvant chemotherapy and interval cytoreductive surgery(NACT-ICS)). Moreover, outcome of surgery was compared between geographical regions. Multilevel logistic regression was used to assess whether existing variation is explained by geographical region and case-mix factors.Results: Overall, 6,741 patients were diagnosed with FIGO IIIC or IV disease. There were no differences in the percentage of patients that received any form of treatment between the geographical regions(range 80-86%, P=0.162). In patients that received cytoreductive surgery and chemotherapy, a significant variation between the geographical regions was observed in the use of PCS and NACT-ICS(PCS: 24-48%, P Conclusion: We observed a significant variation in treatment approach for advanced EOC between geographical regions in the Netherlands. Furthermore, the probability to achieve no residual disease differed significantly between regions, regardless of treatment sequence. This may suggest that surgical outcomes can be improved across geographical regions. (C) 2019 Elsevier Ltd, BASO similar to The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.

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AIM: To validate tissue microarray (TMA) for endometrial cancer by comparing immunohistochemical staining results of triplicate core biopsies on TMA with the results of full-section analysis. METHODS: The study material consisted of slides and selected tissue blocks of 41 patients with endometrioid cancer of the endometrium. A TMA was constructed. Both the TMA and the slides were stained with the same antibodies against progesterone receptor (PR), oestrogen receptor, p53 and epithelial membrane antigen (EMA). Concordance between results was expressed as the kappa statistic. RESULTS: Concordance between the staining results of TMA and whole slides was good for PR (kappa = 0.69), oestrogen receptor (kappa = 0.78), p53 (kappa = 0.81) and EMA (kappa = 0.72). Concordance between the results on TMA and slides depends on the number of assessable cores per tumour. Three assessable cores per case result in outcomes that are at least 94% similar to those achieved using conventional tissue sections with a two-class scoring system. This is independent of focal or diffuse staining patterns. CONCLUSION: TMA is a useful tool for further analysis of the molecular pathways in endometrial cancer. The effect of selection has to be taken into account when the prognostic value of protein expression on TMA is determined

BACKGROUND Despite changes in technique, morbidity after surgical treatment for vulvar cancer is considerable and mainly related to the groin dissection. Primary radiotherapy to the groin is expected to result in lower morbidity. However, studies on the efficacy of primary radiotherapy for the groins in terms of groin recurrences and survival show conflicting results. OBJECTIVES To determine whether the effectiveness and safety of primary radiotherapy to the inguino-femoral lymph nodes is comparable with surgery SEARCH STRATEGY The literature search was carried out using the criteria set by the Cochrane Gynaecological Cancer Group. A MEDLINE and EMBASE search using the Mesh Heading 'vulvar neoplasms' and textword 'vulva' was performed. Publications on the effectiveness of primary radiotherapy treatment of early squamous cell carcinoma of the vulva were selected. SELECTION CRITERIA TYPE OF STUDY Randomized clinical trials, case-control and observational studies of primary radiotherapy of the groin Type of participants: Patients with early squamous cell cancer of the vulva Type of interventions: inguino-femoral lymph node dissection and primary radiotherapy of the inguino-femoral lymph nodes. Type of outcome measurements: incidence of groin recurrences, survival and morbidity DATA COLLECTION AND ANALYSIS Two reviewers independently assessed study quality and extracted results MAIN RESULTS Out of nine reviewed papers only three met the selection criteria. From these studies, (one randomised controlled trial ?RCT? one case-control and one observational study) it became clear from the RCT that the incidence of groin recurrences after primary radiotherapy is higher compared with surgery. survival was also worse in the radiotherapy group. The other two studies showed a higher than expected number of groin recurrences after primary radiotherapy. Morbidity after primary radiotherapy was lower compared with surgery. The conclusion of the RCT was criticized on the grounds of the depth of the radiotherapy administered. The depth of 3 cm used in the RCT, is too shallow to administer an optimal dose to the deeper groin nodes. REVIEWER'S CONCLUSIONS As shown in an RCT, primary radiotherapy to the groin results in less morbidity but also in a higher number of groin recurrences compared with surgery. Although the technique of radiotherapy in the RCT was criticized, other uncontrolled data do not give evidence for a similar or better groin control for radiotherapy when compared to surgery. This means that surgery is still to be considered the cornerstone of therapy for the groin nodes in women with vulvar cancer. Individual patients not fit enough to withstand surgery can be treated with primary radiotherapy.

Objectives: To validate the results of a previous study with the tissue microarray technology showing that cyclooxygenase 2 (COX-2) overexpression and absent caspase 3 expression are associated with poor disease-specific survival in univariate analysis. Methods: The study group comprised 80 consecutive patients with vulva cancer treated in the period from 1999 to 2003 in a university hospital. A tissue microarray with 3 tumor tissue cores per patient was constructed and stained with antibodies against COX-2, caspase 3, epidermal growth factor receptor, p16(INK4), cyclin D1, and Ki-67. The impact of the expression of these protein markers and selected clinicopathologic variables on disease-specific as well as disease-free survival was measured. Cox proportional hazard model was used for both univariate and multivariate analyses. Results: In multivariate analysis, lymph node metastases and strong COX-2 expression were related to disease-free (hazard ratio [HR], 8.33, 95% confidence interval [CI], 2.97-23.36; P

Objectives: The aim of the current study was, first, to determine whether laterality of lymph node metastases has prognostic significance, independent of the number of lymph node metastases. Second was to determine the prognostic significance of extracapsular spread irrespective of the number of lymph node metastases. Methods: Data on 134 patients with stage III/IVA vulva cancer from 1982 till 2004 and treated with curative intent in either the Academic Medical Centre in Amsterdam or the Mercy Hospital for Women in Melbourne were reviewed. The impact of the number of lymph node metastases, extracapsular spread, and bilateral existence of lymph node metastases on survival was determined. Results: The bilateral presence of lymph node metastases is not a significant predictor for survival if a correction is made for the number of lymph node metastases (hazards ratio, 1.3 1; 95% confidence interval, 0.68-2.51; P = 0.420). If extracapsular spread is put into the model as well, this is the only parameter of prognostic significance in multivariate analysis (hazards ratio, 5.27; 95% confidence interval, 2.60-10.67; P

The aim of this study is to determine immunohistochemical markers with prognostic significance for disease-specific survival in patients with squamous cell cancer of the vulva. The study material consisted of slides and paraffin blocks of 50 vulvectomy specimens. A tissue microarray was constructed and stained with 16 antibodies. The impact of lymph node metastases, size of tumor, vascular space involvement, and the marker expression on disease-specific survival was calculated. In univariate analysis lymph node metastases, tumor size more than 4 cm, vascular space involvement, strong cyclooxygenase 2 expression, and absent Caspase 3 expression were significantly associated with disease-specific survival. In a multivariate analysis, poor disease-specific survival is independently associated with absent Caspase 3 expression (hazard ratio, 0.2; 95% confidence interval, 0.04-0.97; P = 0.045). Five-year survival was 86% in patients with tumors positive for Caspase 3 (n = 20) and drops to 64% in patients with Caspase 3-negative tumors (n = 30). In this test set, cyclooxygenase 2 and Caspase 3 seem to be immunohistochemical markers with prognostic significance for vulva cancer. The results have to be validated.

Objective To evaluate the feasibility, toxicity, and pharmacokinetics in the maternal and fetal compartments during chemotherapy in a pregnant patient with cervical cancer. Design Case report. Setting University Hospital. Patient A 35-year-old woman was diagnosed with an adenocarcinoma FIGO stage IB1 of the cervix uteri at 14 weeks' gestation with twin pregnancy. Intervention(s) A laparoscopic transperitoneal pelvic lymphadenectomy was performed at 15 weeks' gestation There was no evidence of lymph node metastases (0/19). The patient decided to continue her pregnancy. Three cycles of neoadjuvant chemotherapy consisting of cisplatin during the second and third trimester were given and well tolerated. Amniocentesis was performed at the time of the second cisplatin cycle. Main Outcome Measure(s) and Result(s) The concentration in the amniotic fluid samples reached 10% of the maternal blood levels at this time. At 32 weeks' gestation, a Caesarean section followed by radical hysterectomy was performed. The twins developed normally and displayed no chemotherapically related side effects. At the time of delivery, the corresponding concentration in the amniotic fluid was approximately one-third of the umbilical cord levels. Conclusion(s) To our knowledge, this is the first report quantifying the amount of transplacental transport of cisplatin during pregnancy in vivo. One-tenth of the maternal serum concentration was detected in the amniotic fluid; the concentration of cisplatin in the umbilical cord was three times higher than in the amniotic fluid.