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The histopathologic features of adult granulosa cell tumors (AGCTs) are relatively nonspecific, resulting in misdiagnosis of other cancers as AGCT, a problem that has not been well characterized. FOXL2 mutation testing was used to stratify 336 AGCTs from three European centers into three categories: 1) FOXL2 mutant molecularly defined AGCT (MD-AGCT) (n = 256 of 336), 2) FOXL2 wild-type AGCT (n = 17 of 336), 3) misdiagnosed other tumor types (n = 63 of 336). All statistical tests were two-sided. The overall and disease-specific survival of the misdiagnosed cases was lower than in the MD-AGCTs (P < .001). The misdiagnosed cases accounted for 71.9% of disease-specific deaths within five years. In the population-based cohort, overall survival of MD-AGCT patients was not different from age-matched, population-based controls. Even though 35.2% of all the MD-AGCT patients in our study experienced a relapse, AGCT is usually an indolent disease. The historical, premolecular data underpinning our clinical understanding of AGCT was likely skewed by inclusion of misdiagnosed cases, and future management strategies should reflect the potential for surgical cure and long survival even after relapse. [ABSTRACT FROM AUTHOR]

Background and purpose We investigated the effects of socio-demographic, treatment- and tumor-specific determinants on the risk of developing a second malignancy among patients treated for cervical cancer. Material and methods We included patients with a first cervical cancer (N = 12,048) from the Netherlands Cancer Registry (NCR), 1989-2008. Standardized incidence ratios (SIR) and absolute excess risks (AER) per 10,000 person-years were calculated to estimate the burden of second cancers in cervical cancer survivors. Incidence rate ratios (IRR) were computed to identify predictors for second cancers among cervical cancer survivors. Results During the study period, 676 (5.6%) patients were diagnosed with a second cancer. Smoking-related cancers contributed the most to the overall burden of second cancers (AER = 21) and risks remained elevated after 10 years of follow-up (SIR = 1.8, 95% CI: 1.4-2.2), yet it decreased markedly in the younger birth cohorts. Cervical cancer survivors who underwent radiotherapy were at higher risk for a second tumor when compared to those without radiotherapy, especially at smoking-related sites (IRR = 1.6 (1.2-2.3)). Conclusion Patients with cervical cancer had a significantly increased risk for a second cancer compared to the general population, especially for smoking- and irradiation-related tumors. Long-term follow-up suggested the importance of smoking cessation and the benefits of counseling cervical cancer patients accordingly, particularly those who received radiotherapy. [ABSTRACT FROM AUTHOR]

Introduction: As a consequence of ovarian cancer and its treatment, many women with ovarian cancer have to deal with reduced physical function, fatigue, and loss of weight and/or muscle mass, compromising quality of life. Exercise and dietary interventions can positively influence body composition, physical fitness and function, and fatigue in patients with cancer. However, there are no data from randomised controlled trials on the effectiveness of exercise and dietary interventions in patients with ovarian cancer. Due to a complex disease trajectory, a relatively poor survival and distinct disease-induced and treatment-induced side effects, it is unclear whether exercise and dietary interventions that were shown to be feasible and effective in other types of cancer produce comparable results in patients with ovarian cancer. The aim of this article is to present the design of the multicentre randomised controlled Physical Activity and Dietary intervention in OVArian cancer trial and to describe how the exercise and dietary intervention is tailored to specific comorbidities and disease-induced and treatment-induced adverse effects in patients with ovarian cancer., Methods and Analysis: Adult women with primary epithelial ovarian cancer who are scheduled to undergo first-line (neo)adjuvant chemotherapy (n=122) are randomly allocated to a combined exercise and dietary intervention or a usual care control group during chemotherapy. Primary outcomes are body composition, physical function and fatigue. Outcome measures will be assessed before the start of chemotherapy, 3 weeks after completion of chemotherapy and 12 weeks later. The exercise and dietary intervention was tailored to ovarian cancer-specific comorbidities and adverse effects of ovarian cancer and its treatment following the i3-S strategy., Ethics and Dissemination: This study has been approved by the medical ethical committee of the Amsterdam UMC (reference: 018). Results of the study will be published in international peer-reviewed journals., Trial Registration Number: Netherlands Trial Registry (NTR6300)., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)

Objective: This study aimed to describe the pattern of recurrence and survival related to prognostic variables, including type of surgery as a clinical variable, in patients surgically treated for early cervix cancer., Methods: Records of 2124 patients who underwent a radical hysterectomy for International Federation of Gynaecology and Obstetrics stage I/IIA cervical cancer between 1982 and 2011 were reviewed. Clinical-pathologic prognostic variables, also including extent of parametrectomy, were identified and used in a multivariable Cox proportional hazard model to explore associations between disease-free survival (DFS) and prognostic variables., Results: The 5-year DFS for the total group was 86%. Large tumor diameter, nonsquamous histology, lymph node metastases, parametrial involvement, lymph vascular space invasion, deep stromal invasion, and less radical surgery were independent poor prognostic variables for survival. Disease-free survival was independently associated with the type of radical hysterectomy with pelvic lymphadenectomy in favor of more radical parametrectomy (hazard ratio, 2.0; 95% confidence interval, 1.6-2.5). This difference was not found in tumors with a diameter of at least 20 mm., Conclusions: This study confirms that variables such as large tumor diameter, nonsquamous histology, lymph vascular space invasion, deep stromal invasion, positive lymph nodes, and parametrial infiltration are poor prognostic variables in early cervix cancer treated by surgery. The extent of parametrectomy had no influence on survival in tumors of 20 mm or less. For larger tumors, a more radical hysterectomy might be associated with better DFS. Taking into account the possible bias in this study as a result of its retrospective design, ideally a prospective cohort study with clear definition of radicality is necessary to answer this important clinical question.

Background: Standard treatment of advanced ovarian cancer is surgery and chemotherapy. The goal of surgery is to remove all macroscopic tumour, as the amount of residual tumour is the most important prognostic factor for survival. When removal off all tumour is considered not feasible, neoadjuvant chemotherapy (NACT) in combination with interval debulking surgery (IDS) is performed. Current methods of staging are not always accurate in predicting surgical outcome, since approximately 40% of patients will have more than 1 cm residual tumour after primary debulking surgery (PDS). In this study we aim to assess whether adding laparoscopy to the diagnostic work-up of patients suspected of advanced ovarian carcinoma may prevent unsuccessful primary debulking surgery for ovarian cancer., Methods: Multicentre randomized controlled trial, including all gynaecologic oncologic centres in the Netherlands and their affiliated hospitals. Patients are eligible when they are planned for PDS after conventional staging. Participants are randomized between direct PDS or additional diagnostic laparoscopy. Depending on the result of laparoscopy patients are treated by PDS within three weeks, followed by six courses of platinum based chemotherapy or with NACT and IDS 3-4 weeks after three courses of chemotherapy, followed by another three courses of chemotherapy. Primary outcome measure is the proportion of PDS's leaving more than one centimetre tumour residual in each arm. In total 200 patients will be randomized. Data will be analysed according to intention to treat., Discussion: Patients who have disease considered to be resectable to less than one centimetre should undergo PDS to improve prognosis. However, there is a need for better diagnostic procedures because the current number of debulking surgeries leaving more than one centimetre residual tumour is still high. Laparoscopy before starting treatment for ovarian cancer can be an additional diagnostic tool to predict the outcome of PDS. Despite the absence of strong evidence and despite the possible complications, laparoscopy is already implemented in many countries. We propose a randomized multicentre trial to provide evidence on the effectiveness of laparoscopy before primary surgery for advanced stage ovarian cancer patients., Trial Registration: Netherlands Trial Register number NTR2644.

Background: Human papillomavirus (HPV) testing is more sensitive for the detection of high-grade cervical lesions than is cytology, but detection of HPV by DNA screening in two screening rounds 5 years apart has not been assessed. The aim of this study was to assess whether HPV DNA testing in the first screen decreases detection of cervical intraepithelial neoplasia (CIN) grade 3 or worse, CIN grade 2 or worse, and cervical cancer in the second screening., Methods: In this randomised trial, women aged 29-56 years participating in the cervical screening programme in the Netherlands were randomly assigned to receive HPV DNA (GP5+/6+-PCR method) and cytology co-testing or cytology testing alone, from January, 1999, to September, 2002. Randomisation (in a 1:1 ratio) was done with computer-generated random numbers after the cervical specimen had been taken. At the second screening 5 years later, HPV DNA and cytology co-testing was done in both groups; researchers were masked to the patient's assignment. The primary endpoint was the number of CIN grade 3 or worse detected. Analysis was done by intention to screen. The trial is now finished and is registered, number ISRCTN20781131., Findings: 22,420 women were randomly assigned to the intervention group and 22 518 to the control group; 19 999 in the intervention group and 20,106 in the control group were eligible for analysis at the first screen. At the second screen, 19 579 women in the intervention group and 19,731 in the control group were eligible, of whom 16,750 and 16,743, respectively, attended the second screen. In the second round, CIN grade 3 or worse was less common in the intervention group than in the control group (88 of 19 579 in the intervention group vs 122 of 19,731 in the control group; relative risk 0·73, 95% CI 0·55-0·96; p=0·023). Cervical cancer was also less common in the intervention group than in the control group (four of 19 579 in the intervention group vs 14 of 19,731; 0·29, 0·10-0·87; p=0·031). In the baseline round, detection of CIN grade 3 or worse did not differ significantly between groups (171 of 19 999 vs 150 of 20,106; 1·15, 0·92-1·43; p=0·239) but was significantly more common in women with normal cytology (34 of 19,286 vs 12 of 19,373; 2·85, 1·47-5·49; p=0·001). Furthermore, significantly more cases of CIN grade 2 or worse were detected in the intervention group than in the control group (267 of 19 999 vs 215 of 20,106; 1·25, 1·05-1·50; p=0·015). In the second screen, fewer HPV16-positive CIN grade 3 or worse were detected in the intervention group than in the control group (17 of 9481 vs 35 of 9354; 0·48, 0·27-0·85; p=0·012); detection of non-HPV16-positive CIN grade 3 or worse did not differ between groups (25 of 9481 vs 25 of 9354; 0·99, 0·57-1·72; p=1·00). The cumulative detection of CIN grade 3 or worse and CIN grade 2 or worse did not differ significantly between study arms, neither for the whole study group (CIN grade 3 or worse: 259 of 19 999 vs 272 of 20,106; 0·96, 0·81-1·14, p=0·631; CIN grade 2 or worse: 427 of 19 999 vs 399 of 20,106; 1·08, 0·94-1·24; p=0·292), nor for subgroups of women invited for the first time (CIN grade 3 or worse in women aged 29-33 years: 102 of 3139 vs 105 of 3128; 0·97, 0·74-1·27; CIN grade 2 or worse in women aged 29-33 years: 153 of 3139 vs 151 of 3128; 1·01, 0·81-1·26; CIN grade 3 or worse in women aged 34-56 years: 157 of 16,860 vs 167 of 16 978; 0·95, 0·76-1·18; CIN grade 2 or worse in women aged 34-56 years: 274 of 16,860 vs 248 of 16 978; 1·11, 0·94-1·32)., Interpretation: Implementation of HPV DNA testing in cervical screening leads to earlier detection of clinically relevant CIN grade 2 or worse, which when adequately treated, improves protection against CIN grade 3 or worse and cervical cancer. Early detection of high-grade cervical legions caused by HPV16 was a major component of this benefit. Our results lend support to the use of HPV DNA testing for all women aged 29 years and older., Funding: Zorg Onderzoek Nederland (Netherlands Organisation for Health Research and Development)., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Alterations in transforming growth factor-beta signaling, due to a decrease in Smad2 and especially Smad4 expression, has primarily been reported in pancreatic and colorectal cancers, although loss of the chromosomal region 18q21.1, containing the loci of Smad2 and Smad4, is among the most frequent molecular alterations in cervical cancer. The aim of our study was to investigate whether decreased Smad2 and Smad4 protein expression in primary cervical cancers is associated with molecular alterations at 18q21.1, mutations in the functional domains of Smad2 and Smad4 or hypermethylation, and to assess the biological relevance of decreased Smad2 and Smad4 expression. Subsequently, Smad2, Smad4 and p21 protein expression was determined by immunohistochemistry in 117 primary cervical carcinomas, assembled in a tissue array. Smad signaling was shown to be associated with p21 mRNA expression. All the tumors expressed Smad2 or Smad4. Weak cytoplasmic Smad2 or weak cytoplasmic Smad4 expression could not be attributed to loss of heterozygosity at 18q21.1. Despite weak/moderate Smad2 expression and absent nuclear Smad4 expression, the coding regions of the functional MH1 and MH2 domains of Smad2 and Smad4 were unchanged, as assessed by sequence analysis. The Smad4 promoter region was unmethylated in tumor samples with weak/moderate cytoplasmic Smad4 expression. Remarkably, both weak cytoplasmic Smad4 expression and absent nuclear Smad4 expression significantly correlated with poor disease-free (P=0.003 and P=0.003, respectively) and overall 5-year survival (P=0.003 and P=0.010, respectively). Our findings support the hypothesis that Smad4 is a target molecule for functional inactivation in cervical cancer.