Diagnostic accuracy and clinical value of [68Ga]Ga-FAPI-46 PET/CT for staging patients with ovarian cancer: study protocol for a prospective clinical trial.

BACKGROUND: [18F]Fluorodeoxyglucose ([18F]FDG) positron emission tomography (PET) is recommended during diagnostic work-up for ovarian cancer; however, [18F]FDG PET has several inherent limitations. The novel oncologic PET-tracer fibroblast activation protein inhibitor (FAPI) has demonstrated promising results in multiple cancer types, including ovarian cancer, and could overcome the limitations of [18F]FDG PET; however, high-quality clinical studies are lacking. The primary objective of the present study is to compare the diagnostic accuracy of [68Ga]Ga-FAPI-46 PET/CT and [18F]FDG PET/CT in ovarian cancer patients and to investigate how this potential difference impacts staging and patient management. METHODS AND DESIGN: Fifty consecutive ovarian cancer patients will be recruited from Aalborg University Hospital, Denmark. This study will be a single-center, prospective, exploratory clinical trial that adheres to the standards for reporting diagnostic accuracy studies (STARD). This study will be conducted under continuous Good Clinical Practice monitoring. The eligibility criteria for patients are as follows: (1) biopsy verified newly diagnosed ovarian cancer or a high risk of ovarian cancer and referred for primary staging with [18F]FDG PET/CT; and (2) resectable disease, i.e., candidate for primary debulking surgery or neoadjuvant chemotherapy followed by interval debulking surgery. All recruited study subjects will undergo [68Ga]Ga-FAPI-46 PET/CT at primary staging, before primary debulking surgery or neoadjuvant chemotherapy (Group A + B), in addition to conventional imaging (including [18F]FDG PET/CT). Study subjects in Group B will undergo an additional [68Ga]Ga-FAPI-46 PET/CT following neoadjuvant chemotherapy prior to interval debulking surgery. The results of the study-related [68Ga]Ga-FAPI-46 PET/CTs will be blinded, and treatment allocation will be based on common clinical practice in accordance with current guidelines. The histopathology of surgical specimens will serve as a reference standard. A recruitment period of 2 years is estimated; the trial is currently recruiting. DISCUSSION: To our knowledge, this trial represents the largest, most extensive, and most meticulous prospective FAPI PET study conducted in patients with ovarian cancer thus far. This study aims to obtain a reliable estimation of the diagnostic accuracy of [68Ga]Ga-FAPI-46 PET/CT, shed light on the clinical importance of [68Ga]Ga-FAPI-46 PET/CT, and examine the potential applicability of [68Ga]Ga-FAPI-46 PET/CT for evaluating chemotherapy response. TRIAL REGISTRATION: clinicaltrials.gov: NCT05903807, 2nd June 2023; and euclinicaltrials.eu EU CT Number: 2023-505938-98-00, authorized 11th September 2023.

The timing of venous thromboembolism in ovarian cancer patients: A nationwide Danish cohort study.

BACKGROUND AND AIM: Venous thromboembolism (VTE) is associated with excess mortality and morbidity in cancer, and is influenced by patient-, tumor-, and treatment-related factors. We aimed to investigate the impact of such factors in a national cohort of patients with epithelial ovarian cancer (EOC). METHODS: Patients in the Danish Gynecologic Cancer Database (DGCD) with EOC from 2005 to 2014 were followed from time of diagnosis to VTE, or censoring. Surgery, chemotherapy, and vascular epithelial growth factor (VEGF)-inhibitors were included as time-varying exposures in Cox proportional hazard regression models. RESULTS: A total of 551 VTE events were registered in 4991 EOC patients. Median follow-up time was 2.9 years. The 2-year cumulative incidence of VTE was 7.2%. Patients were at highest risk during the first year after EOC diagnosis. Previous VTE was associated with a hazard ratio (HR) of 3.26 (95% confidence interval [CI] 2.42-4.39). Exposure to major pelvic surgery was associated with a HR of 3.21 (95% CI 2.29-4.50). Exposure to chemotherapy or (VEGF)-inhibitors were associated with HRs of 1.91 (95% CI 1.56-2.33) and 1.05 (95% CI 0.57-1.93), respectively. Hazard ratios for patients with clear cell histopathology was 1.46 (95% CI 0.97-2.20) and 2.42 for International Federation of Gynaecology and Obstetrics stage III--IV (95% CI 1.93-3.03). CONCLUSIONS: EOC is associated with a high risk of VTE, particularly within the first year after diagnosis. Major pelvic surgery and chemotherapy were strongly associated with VTE. Person-related risk factors were increasing age and previous VTE. Advanced stage was an independent tumor-related risk factor. These findings support the indication for thrombosis prophylaxis during chemotherapy.

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.

Venous thromboembolism in epithelial ovarian cancer. A prospective cohort study.

OBJECTIVE: To determine the incidence of symptomatic and incidental venous thromboembolism (VTE) at time of diagnosis and throughout the first year, in patients with suspected epithelial ovarian cancer (EOC). METHODS: Patients were recruited consecutively in the gynecological outpatient clinic at Aalborg University Hospital, Denmark from December 2014 to May 2017. All patients underwent a whole leg compression ultrasound scan (CUS), Computed Tomography (CT) of the thorax in arterial phase at time of inclusion, to be able to diagnose deep vein thrombosis (DVT) and pulmonary embolism (PE), respectively. Patients were followed and systematically screened for VTE throughout 12 months. RESULTS: Ninety-seven patients with suspected EOC were enrolled in the study and followed up. Within the group of EOC patients (N = 53) eleven were diagnosed with VTE during the first year from EOC diagnosis, the incidence of VTE at time of diagnosis was low (2/53-3.8%). No patients with borderline or benign ovarian neoplasms were diagnosed with VTE. One EOC patient had a VTE during the postoperative period and further eight EOC patients were diagnosed with VTE within the first year, during periods undergoing non-surgical cancer treatment. Median time to VTE was 87 days. CONCLUSIONS: The one year cumulative incidence of VTE in EOC patients was 20.8% with a low incidence at time of diagnosis. A substantial number of VTE cases (73%) appeared during periods of non-surgical oncologic treatment. Future research should focus on risk factors and timing of VTE in EOC patients, as this could have important implications for future prophylaxis guidelines.

Endometrial cancer does not increase the 30-day risk of venous thromboembolism following hysterectomy compared to benign disease. A Danish National Cohort Study.

OBJECTIVES: We aimed to clarify if endometrial cancer patients are at higher risk of venous thromboembolism (VTE) following hysterectomy, compared to patients undergoing hysterectomy for benign gynecological disease. METHODS: In a nationwide registry-based cohort study, patients undergoing hysterectomy for endometrial cancer or benign disease were followed 30 days after surgery. The Danish Gynecological Cancer Database (DGCD) and the Danish National Patient Register (DNPR) were linked with four other administrative registries to describe the population and retrieve data on venous thromboembolism and mortality. Multivariable logistic regression models were used to estimate odds ratios (ORs) for 30-day postoperative VTE. RESULTS: We identified 5513 patients with endometrial cancer, and 45,825 patients with benign disease undergoing hysterectomy in the period 2005-2014. The overall incidence of 30-day VTE following hysterectomy was 0.2% (103/51,338). Thirty (0.5%) patients with endometrial cancer and 73 (0.16%) patients with benign disease developed VTE. In a multivariable logistic regression analysis, significant predictors of 30-day OR for VTE were open surgery (minimally invasive surgery vs. open: OR = 0.46; 95% CI, 0.30-0.71; p < 0.001), lymphadenectomy (OR = 4.00; 95% CI, 1.89-8.46; p < 0.001), BMI > 40 (OR = 2.34;95% CI, 1.10-5.01; p = 0.03) and previous VTE (OR = 34; 95% CI, 22.7-51.3; p < 0.001). There was no statistically significant difference in the 30-day OR for VTE in endometrial cancer compared to benign disease (OR = 1.47; 95% CI, 0.74-2.91; p = 0.27). CONCLUSIONS: This study did not identify endometrial cancer to be an independent risk factor for VTE following hysterectomy compared to benign disease. We identified open surgery, lymphadenectomy, BMI above 40 and previous VTE as independent risk factors for 30-day postoperative VTE.

Venous Thromboembolic Complications to Hysterectomy for Benign Disease: A Nationwide Cohort Study.

STUDY OBJECTIVE: To estimate the risk of venous thromboembolic complications after abdominal, laparoscopic, and vaginal hysterectomy when performed for benign disorders. DESIGN: A nationwide cohort study (Canadian Task Force classification II-2). SETTING: Data from Danish national registers on all women undergoing hysterectomy for benign conditions from 1996 to 2015. PATIENTS: Women aged 18 years and older who underwent hysterectomy for benign disease were stratified into 3 groups according to the hysterectomy approach: abdominal, laparoscopic, or vaginal. INTERVENTIONS: Hysterectomy. MEASUREMENTS AND MAIN RESULTS: Eighty-nine thousand nine hundred thirty-one women met the inclusion criteria. Venous thromboembolism (VTE) as a diagnosis or cause of death was identified. The risk of postoperative VTE was examined with Cox proportional hazard models adjusting for age, surgical approach, and relevant comorbidities. The mean age was 49.9, 47.9, and 54.3 years for women with abdominal, laparoscopic, and vaginal hysterectomy, respectively. The crude incidences of VTE within 30 days after hysterectomy were 0.24% (n = 142), 0.13% (n = 12), and 0.10% (n = 21). The most important predictors of VTE were the approach to hysterectomy and a history of thromboembolic disease. In the multivariable analysis, the risk of VTE was significantly reduced with laparoscopic hysterectomy (hazard ratio [HR] = 0.51; 95% confidence interval [CI], 0.28-0.92; p = .03) and vaginal hysterectomy (HR = 0.39; 95% CI, 0.24-0.63; p < .001) when compared with the abdominal procedure. Data on postoperative heparin thromboprophylaxis were available in 53 566 patients, and the adjusted HR was 0.63 (95% CI, 0.42-0.96; p = .03) in patients receiving heparin thromboprophylaxis. CONCLUSION: The 30-day cumulative incidence of VTE after hysterectomy for benign conditions was low overall (0.19%). Laparoscopic hysterectomy and vaginal hysterectomy carry a lower risk than the abdominal procedure. Postoperative heparin thromboprophylaxis significantly reduces the risk of VTE and should be considered, especially if risk factors are present.

Association of Previous Cesarean Delivery With Surgical Complications After a Hysterectomy Later in Life.

IMPORTANCE: In recent decades, the global rates of cesarean delivery have rapidly increased. Nonetheless, the influence of cesarean deliveries on surgical complications later in life has been understudied. OBJECTIVE: To investigate whether previous cesarean delivery increases the risk of reoperation, perioperative and postoperative complications, and blood transfusion when undergoing a hysterectomy later in life. DESIGN, SETTING, AND PARTICIPANTS: This registry-based cohort study used data from Danish nationwide registers on all women who gave birth for the first time between January 1, 1993, and December 31, 2012, and underwent a benign, nongravid hysterectomy between January 1, 1996, and December 31, 2012. The dates of this analysis were February 1 to June 30, 2016. EXPOSURE: Cesarean delivery. MAIN OUTCOMES AND MEASURES: Reoperation, perioperative and postoperative complications, and blood transfusion within 30 days of a hysterectomy. RESULTS: Of the 7685 women (mean [SD] age, 40.0 [5.3] years) who met the inclusion criteria, 5267 (68.5%) had no previous cesarean delivery, 1694 (22.0%) had 1 cesarean delivery, and 724 (9.4%) had 2 or more cesarean deliveries. Among the 7685 included women, 3714 (48.3%) had an abdominal hysterectomy, 2513 (32.7%) had a vaginal hysterectomy, and 1458 (19.0%) had a laparoscopic hysterectomy. In total, 388 women (5.0%) had a reoperation within 30 days after a hysterectomy. Compared with women having vaginal deliveries, fully adjusted multivariable analysis showed that the adjusted odds ratio of reoperation for women having 1 previous cesarean delivery was 1.31 (95% CI, 1.03-1.68), and the adjusted odds ratio was 1.35 (95% CI, 0.96-1.91) for women having 2 or more cesarean deliveries. Perioperative and postoperative complications were reported in 934 women (12.2%) and were more frequent in women with previous cesarean deliveries, with adjusted odds ratios of 1.16 (95% CI, 0.98-1.37) for 1 cesarean delivery and 1.30 (95% CI, 1.02-1.65) for 2 or more cesarean deliveries. Blood transfusion was administered to 195 women (2.5%). Women having 2 or more cesarean deliveries had an adjusted odds ratio for receiving blood transfusion of 1.93 (95% CI, 1.21-3.07) compared with women having no previous cesarean delivery. CONCLUSIONS AND RELEVANCE: Women with at least 1 previous cesarean delivery face an increased risk of complications when undergoing a hysterectomy later in life. The results support policies and clinical efforts to prevent cesarean deliveries that are not medically indicated.

Proteomic profiling of peritoneal rinse fluid sediment separates patients with ovarian cancer from women admitted for cesarean section. A pilot study.

OBJECTIVE: There is a great need for additional approaches to discover putative biomarkers for ovarian cancer that accounts for 5% of all cancer deaths among women and is the leading cause of deaths among gynecologic malignancies in the United States. METHODS: Peritoneal rinse fluid sediment from seven patients having ovarian cancer and four women admitted for cesarean section was analysed by proteomic techniques using two-dimensional gel electrophoresis and tandem mass spectrometry. RESULTS: Sixteen protein spots were found to be significantly and highly up-regulated in samples from cancer patients as compared with the cesarean section group. Nine of the protein spots were identified as C-terminal fragments of fibrinogen-ß (spot Nos. 5404 and 5408), haptoglobin-α2 (spot Nos. 4101 and 6103), haptoglobin-ß (spot Nos. 2502, 2504, 3502 and 4401) and transthyretin (spot No. 4002). Generally, several isoelectric variants were present of each protein. The protein concentration in the sediment of spot No. 506 and spot No. 5404 (identified as fibrinogen-ß) was significantly (p < 0.05) and negatively correlated with survival rate of the ovarian cancer patients while for three of the spots a borderline significant (p < 0.07) negative correlation was found. CONCLUSIONS: It is suggested that further development of this method may give a basis for identifying suitable diagnostic and prognostic biomarkers for ovarian cancer.

The results of treatment of epithelial ovarian cancer after centralisation of primary surgery. Results from North Jutland, Denmark.

OBJECTIVE: The study was performed to evaluate the results of treatment of ovarian carcinoma after the introduction of centralised primary surgery in the County of North Jutland, Denmark. METHOD: Prospective study of consecutive cases of ovarian cancer undergoing primary surgical treatment at the Gynecologic Oncologic Center after the introduction of centralised primary surgery. Results of treatment recorded up to the date of last examination or death. RESULTS: From 1999 to 2002, 107 patients with primary epithelial ovarian cancer underwent primary surgery at the Gynecologic Oncologic Center, Aalborg. This corresponds to 95.5% of patients with invasive carcinoma in the County of North Jutland. All patients with Stage I to Stage IIIB disease had a complete, macroscopically radical cytoreduction performed. In patients with Stage III and IV invasive tumors, the optimal debulking rate was 79.5%, and, in Stage IIIC and IV, the optimal debulking rate was 78.2%. Intra-operative and post-operative complications were generally few. Post-operative death, defined as death within 30 days after surgery, was observed in 4 cases (3.7%). After primary surgery, platinum-based chemotherapy was given in most cases. For Stage I to IV invasive cancer, the median survival was 46 months. In patients with Stage IIIC and IV disease, the median survival was 32 months. In optimally debulked Stage IIIC and IV disease, the median survival was 41 months. CONCLUSIONS: The results indicate a survival benefit after introduction of centralised primary surgery. Compared to existing national and regional data on survival in ovarian cancer, the results indicate an increase in median survival for all stages of approximately 15 months. Centralisation of primary surgery to centres with the necessary expertise may be the most significant way to increase survival in ovarian cancer in Denmark.

[Long-term follow-up of women with first-time diagnosis of mild dysplasia detected by cytological examination of the cervix]. / Langtidsopfølgning af kvinder med førstegangsdiagnosen let dysplasi påvist ved cervixcytologisk undersøgelse.

INTRODUCTION: Since 1990, women in Northern Jutland having the cytologic first-time diagnosis of mild dysplasia have been managed according to age-differentiated guidelines. It was the purpose of this study to evaluate these guidelines focusing on compliance, progression, treatment, and follow-up after treatment. MATERIAL AND METHODS: Register-based follow-up study comprising 993 women with the cytologic first-time diagnosis of mild dysplasia entered into the database file of the Department of Pathology of Aalborg Hospital in the period 1990-1991. RESULTS: The first follow-up examination after the initial cytology was performed four months (median) later. The age was negatively associated to the time for the follow-up (p < 0.0001). 18% of the women were later presenting with a diagnosis of at least moderate dysplasia, among whom four cases of invasive cancer stage 1A1 were observed. Age was not significantly associated to the risk of progression (p = 0.32). In contrast, earlier atypical smear was strongly positively related to later progression (p = 0.003). 39% of the women were treated during the observation period. After treatment the first follow-up examination was performed after 20 (median) months. Younger women were examined later than older women (p < 0.0001). 6.1% of the women treated were later diagnosed as having cervix neoplasia. DISCUSSION: 1) Compliance was not optimal. 2) Cytologic follow-up after six months is a safe method in the management of mild dysplasia. 3) Age-differentiated follow-up procedure is not justified. 4) Earlier atypical smear was an important risk factor for progression. 5) The follow-up after treatment should be standardized and EDP monitoring implemented.

Risk of malignancy index in the preoperative evaluation of patients with adnexal masses.

OBJECTIVE: The aim of this study was to evaluate the use of a Risk of Malignancy Index (RMI) in primary evaluation of patients with adnexal masses. METHODS: The RMI is based on menopausal status, ultrasonographic findings, and serum CA 125 level. A cutoff level of 200 was chosen as the threshold for referral for centralized primary surgery. This setup was evaluated by sensitivity, specificity, and positive predictive (PPV) and negative predictive (NPV) values with respect to the ability to distinguish malignant from benign pelvic masses. RESULTS: The sensitivity was 70.6%, specificity 89.3%, PPV 66.1%, and NPV 91.1% for the total material. For the patients undergoing surgery the sensitivity was 70.6%, specificity 87.7%, PPV 66.1%, and NPV 89.8%. If stage I disease is considered "benign" disease, the sensitivity is 95.5%, specificity 87.9%, PPV 57.8%, and NPV 99.1%. CONCLUSIONS: RMI is a simple, easily applicable method in the primary evaluation of patients with adnexal masses. It is usable as a method for selective referral of relevant patients for centralized primary surgery. The method has significant limitations in borderline ovarian tumors, stage I invasive cancers, and nonepithelial tumors. Other methods should be evaluated to increase diagnostic accuracy in these cases.

[Morbidity of infants born to diabetic mothers]. / Sygeligheden hos spaedbørn født af diabetiske mødre.

INTRODUCTION: The pregnancies of diabetic mothers, their deliveries, and complications in relation to the White class are well described. In contrast, very little is known about the morbidity of infants below one year of age, if their mothers suffer from diabetes mellitus. We examined this type of morbidity by analysing hospitalisation after the initial discharge, days with fever, number of contacts to their general practitioner, and increase in weight during the first year of life in relation to the maternal White class. MATERIAL AND METHODS: We carried out a questionnaire-based, follow-up study comprising 217 pregnant women with insulin-dependent diabetes mellitus, who were referred to Aarhus Kommune Hospital/Skejby Sygehus for pregnancy and birth care in the period 1985-1995. RESULTS: We found that 20.3% of the infants had been hospitalised in the first year of life. There was a significant decrease in hospitalisation, fewer visits to the doctor, and fewer days with fever the higher the White class. Infants born of mothers belonging to White class B had the highest median birth weight. DISCUSSION: Infants who are delivered of mothers who suffer from severe diabetes have a similar rate of morbidity in their first year of life to children whose mothers only suffer from a mild type of diabetes.