Follow-up After Loop Electrosurgical Excision of Cervical Intraepithelial Neoplasia: The Use of Combined Cytology and Human Papillomavirus Testing.

OBJECTIVES: The aims of the study were to investigate how many women after 1 or 2 follow-up examinations, based on combined cervical cytology and human papillomavirus (HPV) testing, could finish posttreatment follow-up and continue with the general screening program and to determine the 5-year risk of recurrence in this group. METHODS: This is a prospective observational study that includes women, who underwent loop electrosurgical excision procedure (LEEP) in the North Denmark Region, from January 1, 2012, to May 31, 2014. All included women had histologically verified diagnosis of high-grade cervical intraepithelial neoplasia (CIN 2+) or adenocarcinoma in situ (AIS) before LEEP and posttreatment follow-up with cervical cytology and HPV combination testing. Study period was until October 2019. RESULTS: Totally, 563 women were included in the study. After finishing the posttreatment follow-up, 439 (78%) could continue to the general screening program and 362 of them had a screening during the study period. Six women (1.7%) had either cervical dysplasia and/or HPV infection in the cervical screening, and of these, 3 (0.8%) had high-grade dysplasia corresponding to CIN 2. None was diagnosed with CIN 3, AIS, or invasive carcinoma. One hundred twenty-one women (36%) chose to be screened sooner than recommended in the national guidelines. CONCLUSIONS: Human papillomavirus and cytology combination test after LEEP allows women, irrespective of margin status, safely to continue with the general screening program after a short posttreatment follow-up period. Improved information is mandatory to reduce "opportunistic" screening after finishing posttreatment follow-up.

Spontaneous utero-cutaneous fistula between a benign uterine leiomyoma and abdominal skin: A case report.

The case of a 56-year-old woman with a fibroid uterus who developed utero-cutaneous fistula is presented. The woman was para 0, had an unremarkable medical history, and had no prior diagnosis of a gynecologic pathology, no operative interventions involving the uterine wall or any other risk factor for fistula. Abdominal examination revealed an abdominal mass with overlying deep, purulent ulceration. 18F-FDG PET/CT scan was consistent with uterine leiomyoma, but a differential diagnosis of sarcoma was considered due to the presence of the fistula, patchy increased FDG uptake of the tumor and several mildly enlarged lymph nodes bilaterally in the inguinal and iliac region. Hysterectomy with bilateral salpingo-oophorectomy was performed. Histological diagnosis was of leiomyoma with focal bizarre atypia, degenerative and metaplastic changes and utero-cutaneous fistula. To the best of our knowledge, this is the first case report describing a benign leiomyoma forming a fistula between the uterus and abdominal surface.

Preoperative quantitative sensory testing and robot-assisted laparoscopic hysterectomy for endometrial cancer: can chronic postoperative pain be predicted?

Objectives Chronic postoperative pain is prevalent after robot-assisted laparoscopic hysterectomy for endometrial cancer. Preoperative Quantitative Sensory Testing (QST) has been utilized to identify patients at risk of developing chronic postoperative pain after a range of surgical procedures. The aim of this prospective, observational study was to (1) determine the prevalence of chronic postoperative pain, (2) assess selected preoperative risk factors for chronic postoperative pain, and (3) evaluate if preoperative QST profiling could predict the development of chronic postoperative pain following robot-assisted laparoscopic hysterectomy for endometrial cancer. Methods One-hundred and sixty consecutive patients were included and handheld pressure algometry, cuff pressure algometry, temporal summation of pain, conditioned pain modulation, and heat pain thresholds were assessed prior to surgery. Patients were asked to fill out a questionnaire concerning pain in the pre- and post-operative time period six months after surgery. Chronic postoperative pain was defined as persistent, moderate to severe pain (mean visual analogue scale (VAS)≥3) on a daily basis six months after surgery. Results The prevalence of chronic postoperative pain after robot-assisted laparoscopic hysterectomy for endometrial cancer was of 13.6% (95% CI 8.4-20.4%). Patients that would develop chronic postoperative pain had a lower BMI (p=0.032), a higher prevalence of preoperative pelvic pain (p<0.001), preoperative heat pain hyperalgesia (p=0.043) and a higher level of acute postoperative pain (p<0.001) when compared to patients that would not develop chronic postoperative pain. A logistic regression model demonstrated that the presence of preoperative pelvic pain was a significant, independent predictive risk factor for development of chronic postoperative pain (OR=6.62, 95% CI 2.26-19.44), whereas none of the QST parameters could predict postoperative pain. Conclusions Preoperative QST assessment could not predict the development of chronic postoperative pain despite preoperative heat pain hyperalgesia in patients that would develop chronic postoperative pain.

Chronic Postoperative Pain After Hysterectomy for Endometrial Cancer: A Metabolic Profiling Study.

INTRODUCTION: One out of seven women will develop a state of chronic postoperative pain following robot-assisted hysterectomy for endometrial cancer. Recently, metabolic studies have indicated that circulating lipids and lipoproteins could act as nociceptive modulators and thereby influence the induction and perpetuation of pain. The objectives of this explorative study were (1) to examine the preoperative serologic variations in concentrations of lipids, lipoproteins, and various low-molecular metabolites in patients with and without chronic postoperative pain after robot-assisted hysterectomy and (2) to explore if any of these serological biomarkers were predictive for development of chronic postoperative pain. MATERIALS AND METHODS: The study was designed as a nested case-control study within a cohort of women treated for endometrial cancer with robot-assisted laparoscopic hysterectomy. Twenty-six women with chronic postoperative pain were matched on age and body mass index with fifty-two controls without chronic postoperative pain, and metabolic profiling of preoperatively drawn blood samples from a biobank was performed by means of nuclear magnetic resonance spectroscopy. RESULTS: Nineteen metabolites, including cholesterol, cholesteryl ester, linoleic acid, phospholipids, lipids, and triglycerides had statistically significant higher concentrations in a subgroup of patients who would develop chronic postoperative pain on a later stage compared to the group of patients who would not develop chronic postoperative pain (p < 0.05). A sparse Partial Least Squares-Discriminant Analysis model explained 38.1% of the variance and had a predictive accuracy of 73.1%. CONCLUSIONS: This explorative study substantiates the hypothesis that certain lipids, lipoproteins, and fatty acids are associated with chronic postoperative pain.

Survival after a nationwide adoption of robotic minimally invasive surgery for early-stage cervical cancer - A population-based study.

AIM: Lately, the safety of minimally invasive surgery (MIS) in the treatment of cervical cancer (CC) has been questioned. This study aimed to evaluate the risk of recurrence and survival after a nationwide adoption of robotic MIS for the treatment of early-stage CC in Denmark. METHODS: Population-based data on all Danish women with early-stage CC, who underwent radical hysterectomy January 1st 2005-June 30th 2017 were retrieved from the Danish Gynecologic Cancer Database and enriched with follow-up data on recurrence, death and cause of death. The cohort was divided into two groups according to the year of robotic MIS introduction at each cancer centre. Chi-squared or Fischer test, the Kaplan Meier method and multivariate Cox regression were used for comparison between groups. RESULTS: One thousand one hundred twenty-five patients with CC were included; 530 underwent surgery before (group 1) and 595 underwent surgery after (group 2) the introduction of robotic MIS. The 5-year rate of recurrence was low: 8.2% and 6.3% (p = 0.55) in group 1 and 2, respectively. In adjusted analyses, this corresponded to a five-year disease-free survival, hazard ratio (HR) 1.23 [95% confidence interval (CI) 0.79-1.93]. No difference in site of recurrence (P = 0.19) was observed. The cumulative cancer-specific survival was 94.1% and 95.9% (P = 0.10) in group 1 and 2, respectively, corresponding to a HR 0.60 [95% CI 0.32-1.11] in adjusted analyses. CONCLUSION: In this population-based cohort study, the Danish nationwide adoption of robotic MIS for early-stage CC was not associated with increased risk of recurrence or reduction in survival outcomes.

The clinical importance of BRCAness in a population-based cohort of Danish epithelial ovarian cancer.

OBJECTIVE: Germline mutations in BRCA1/2 genes predict improved survival and sensitivity to treatment with poly(adenosine-diphosphate-ribose) polymerase inhibitors in epithelial ovarian carcinoma. The prognostic importance of other genetic alterations leading to homologous recombination deficiency, collectively BRCAness phenotype, is unresolved. The aim was to analyze the distribution of homologous recombination deficiency in epithelial ovarian carcinoma caused by mutations in a panel of homologous recombination genes (including BRCA1/2) or epigenetic alterations. A further aim was to investigate the prognostic importance of homologous recombination deficiency, the BRCAness phenotype. METHODS: We assessed 380 patient specimens from a Danish population-based epithelial ovarian carcinoma cohort for germline and somatic mutations in 18 different homologous recombination genes, including BRCA1 and BRCA2, using next generation sequencing. Epigenetic alteration due to BRCA1 hypermethylation was assessed by pyrosequencing and BRCA1 protein expression was evaluated by immunohistochemistry. RESULTS: Seventeen percent of patients with epithelial ovarian carcinoma carried a germline (9.8%) and/or somatic (6.3%) mutation in 12 (BRCA1, BRCA2, CHEK2, ATM, RAD51D, EMSY, PALB2, BRIP1, ERCC1, RAD50, ATR, RAD51C) of 18 sequenced homologous recombination genes. The homologous recombination mutation rate was similar among the different histologic subtypes, however the type of mutation (BRCA1/2 and other homologous recombination mutations) differed, p=4×10-4. BRCA1 hypermethylation was present in 7.4% of patient specimens for a total BRCAness phenotype of 23.9%. The BRCAness phenotype was associated with improved overall survival in the high-grade serous carcinoma subgroup with a median overall survival of 4.4 years (95% CI 3.0 to 5.3) versus 2.2 years (95% CI 1.9 to 2.4) in BRCAness wildtype, p=0.0002. Multivariate analysis confirmed an independent prognostic value of the BRCAness phenotype among the high-grade serous carcinoma subgroup, hazard ratio 0.65 (95% CI 0.47 to 0.92), p=0.014. CONCLUSIONS: The BRCAness phenotype is present in almost one-fourth of epithelial ovarian carcinoma and holds important prognostic information. The implications of our findings in relation to poly(adenosine-diphosphate-ribose) polymerase inhibitor treatment call for further investigation.

The Prognostic Value of BRCA1 and PARP Expression in Epithelial Ovarian Carcinoma: Immunohistochemical Detection.

BRCA1/2 mutation status in epithelial ovarian cancer (EOC) presently relies on genetic testing which is resource consuming. Immunohistochemistry is cheap, fairly reproducible, and may identify gene product alterations due to both germline and somatic mutations and other defects along the BRCA gene pathway (BRCAness phenomenon), which is important when treatment with poly (adenosine-diphosphate-ribose) polymerase (PARP) inhibitors is considered. The aim of this study was to investigate immunohistochemical detection of BRCA1 and PARP expression in EOC and their possible prognostic relevance. Tumor tissue from 170 patients with EOC was stained immunohistochemically with BRCA1 and PARP antibodies. Semiquantitative analyses were performed to determine loss of, equivocal, and retained BRCA1 and high versus low PARP protein expression. These parameters were analyzed for relation with patient and clinicopathologic characteristics and overall survival. BRCA1 expression was reduced in 21.2 % of the tumors and 36.5% showed high PARP expression. No correlation between the 2 parameters or between PARP and clinicopathologic features was found. Overall survival was significantly increased in the BRCA1-reduced and equivocal groups [median survival 2.4 y (95% CI, 1.6-6.6) and 4.9 y (95 % CI, 2.3-6.7) vs. 1.5 y (95% CI, 1.3-1.9); P=0.0002]. Multivariate analysis confirmed these findings; hazard ratio=0.53 (95% CI, 0.34-0.81; P=0.0037; loss of BRCA1 expression). In conclusion, immunohistochemical BRCA1 expression in EOC holds considerable prognostic information, whereas PARP expression did not influence the outcome. The results call for validation in prospective trials.

Adjustment of serum HE4 to reduced glomerular filtration and its use in biomarker-based prediction of deep myometrial invasion in endometrial cancer.

BACKGROUND: We investigated the efficacy of circulating biomarkers together with histological grade and age to predict deep myometrial invasion (dMI) in endometrial cancer patients. METHODS: HE4ren was developed adjusting HE4 serum levels towards decreased glomerular filtration rate as quantified by the eGFR-EPI formula. Preoperative HE4, HE4ren, CA125, age, and grade were evaluated in the context of perioperative depth of myometrial invasion in endometrial cancer (EC) patients. Continuous and categorized models were developed by binary logistic regression for any-grade and for G1-or-G2 patients based on single-institution data from 120 EC patients and validated against multicentric data from 379 EC patients. RESULTS: In non-cancer individuals, serum HE4 levels increase log-linearly with reduced glomerular filtration of eGFR ≤ 90 ml/min/1.73 m2. HE4ren, adjusting HE4 serum levels to decreased eGFR, was calculated as follows: HE4ren = exp[ln(HE4) + 2.182 × (eGFR-90) × 10-2]. Serum HE4 but not HE4ren is correlated with age. Model with continuous HE4ren, age, and grade predicted dMI in G1-or-G2 EC patients with AUC = 0.833 and AUC = 0.715, respectively, in two validation sets. In a simplified categorical model for G1-or-G2 patients, risk factors were determined as grade 2, HE4ren ≥ 45 pmol/l, CA125 ≥ 35 U/ml, and age ≥ 60. Cumulation of weighted risk factors enabled classification of EC patients to low-risk or high-risk for dMI. CONCLUSIONS: We have introduced the HE4ren formula, adjusting serum HE4 levels to reduced eGFR that enables quantification of time-dependent changes in HE4 production and elimination irrespective of age and renal function in women. Utilizing HE4ren improves performance of biomarker-based models for prediction of dMI in endometrial cancer patients.

Neoadjuvant chemotherapy as ovarian cancer treatment: ever more used with major regional differences.

INTRODUCTION: The traditional first-line treatment for patients with advanced ovarian cancer with primary debulking surgery (PDS) and adjuvant chemotherapy is controversial as some authors report a potential benefit from the alternative treatment with neoadjuvant chemotherapy (NACT) and interval debulking surgery. The aim of this study was to investigate the use of NACT in Denmark in regard to increased use and regional differences. MATERIAL AND METHODS: Stage IIIC and IV ovarian cancer patients treated in the five Danish tertiary referral centres in the 2005-2010-period were included. The study is based on validated data from The Danish Gynaecological Cancer Database. RESULTS: Of the 1,367 eligible patients 1,069 were treated with PDS and 298 with NACT. In 2005-2007, 11% of patients were treated with NACT. In 2008-2010, this percentage had risen to 30% (p < 0.00001). Between the five referral centres, the use of NACT ranged from 6% to 41% in 2005-2010 (p < 0.00001); from 1 % to 31% in 2005-2007 (p < 0.00001); from 10% to 48% in 2008-2010 (p < 0.00001) and from 9% to 48% in 2010 (p < 0.0008). Patients treated with NACT were significantly older, had inferior ASA scores and Eastern Cooperative Oncology Group performance status compared with the patients from the PDS group. There was no difference between treatments in regard to body mass index, stage IV disease or patients with no co-morbidity. CONCLUSION: The use of NACT as first-line treatment tripled from 2005-2010, but the regional variability was large which calls for a uniform agreement on treatment principles and evaluation. FUNDING: This study was financially supported by grants from The Copenhagen University Hospital Research Foundation, Manufacturer Einar Willumsens Memorial Trust, The Capital Region of Denmark Research Foundation, The Arvid Nilsson Foundation, The King Christian X Foundation, The Dagmar Marshall Foundation, The Danish Research Foundation, and The Hans and Nora Buchard Foundation. TRIAL REGISTRATION: not relevant.

Survival of patients with ovarian cancer in central and northern Denmark, 1998-2009.

OBJECTIVE: To examine time trends of survival and mortality of ovarian cancer in the central and northern Denmark regions during the period 1998-2009. STUDY DESIGN AND SETTING: We conducted a cohort study including women recorded with a first-time diagnosis of ovarian cancer in the Danish National Registry of Patients (DNRP) between 1998 and 2009. Patients were followed for survival through the Danish Civil Registration System. We determined survival stratified by age, and used Cox proportional hazard regression analyses to obtain mortality rate ratios (MRRs) to assess changes over time. RESULTS: We found no improvement in overall ovarian cancer survival between 1998 and 2009. One-year survival was 71% in 1998-2000 and 68% in 2007-2009. Three-year survival declined from 48% in 1998-2000 to 46% in 2007-2009 (predicted), and 5-year survival declined from 40% in 1998-2000 to 37% in 2007-2009 (predicted). Compared with the period 1998-2000, the age-adjusted 1-year MRR was 1.05 (95% confidence interval CI: 0.86-1.28) for the period 2007-2009, and the predicted age-adjusted 3- and 5-year MRRs were 0.96 (95% CI: 0.83-1.12) and 0.99 (95% CI: 0.86-1.14), respectively. Results are not adjusted for tumor stage as this information was not available. We also observed a decline in the annual number of incident ovarian cancer patients during the study period, most pronounced in the youngest age group. CONCLUSION: The survival of ovarian cancer patients did not improve during the study period. This lack of improvement contrasts with the national cancer strategies implemented during this last decade, focusing on improving the survival of ovarian cancer patients.