Circulating cell-free HPV DNA is a strong marker for disease severity in cervical cancer.

For cervical cancer (CC), circulating cell-free HPV DNA (ccfHPV) may establish disease severity. Furthermore, HPV integration has been correlated to viral load and survival. In this study, pre-treatment plasma from 139 CC cases (50 primary surgery patients, 22 primary surgery + adjuvant oncological therapy patients, and 67 primary oncological therapy patients) was collected (2018-2020). Furthermore, plasma from 25 cervical intraepithelial neoplasia grade 3 patients and 15 healthy women (negative controls) were collected. Two next-generation sequencing (NGS) panels were used to establish ccfHPV presence and human papillomavirus type 16 (HPV16) integration status. ccfHPV was detected in four primary surgery (8.0%), eight primary surgery + adjuvant oncology (36.4%), and 54 primary oncology (80.6%) patients. For primary oncology patients with HPV16-related cancer (n = 37), more ccfHPVneg than ccfHPVpos patients had HPV16 integration (P = 0.04), and in patients with HPV16 integration (n = 13), ccfHPVpos patients had higher disease stages than ccfHPVneg patients (P = 0.05). In summary, ccfHPV presence is related to disease severity and may add to the debated Sedlis criteria used for identifying patients for adjuvant oncological therapy. However, ccfHPV detection is influenced by HPV integration status and disease stage, and these factors need to be considered in ccfHPVneg patients.

A federated approach to identify women with early-stage cervical cancer at low risk of lymph node metastases.

OBJECTIVE: Lymph node metastases (pN+) in presumed early-stage cervical cancer negatively impact prognosis. Using federated learning, we aimed to develop a tool to identify a group of women at low risk of pN+, to guide the shared decision-making process concerning the extent of lymph node dissection. METHODS: Women with cervical cancer between 2005 and 2020 were identified retrospectively from population-based registries: the Danish Gynaecological Cancer Database, Swedish Quality Registry for Gynaecologic Cancer and Netherlands Cancer Registry. Inclusion criteria were: squamous cell carcinoma, adenocarcinoma or adenosquamous carcinoma; The International Federation of Gynecology and Obstetrics 2009 IA2, IB1 and IIA1; treatment with radical hysterectomy and pelvic lymph node assessment. We applied privacy-preserving federated logistic regression to identify risk factors of pN+. Significant factors were used to stratify the risk of pN+. RESULTS: We included 3606 women (pN+ 11%). The most important risk factors of pN+ were lymphovascular space invasion (LVSI) (odds ratio [OR] 5.16, 95% confidence interval [CI], 4.59-5.79), tumour size 21-40 mm (OR 2.14, 95% CI, 1.89-2.43) and depth of invasion>10 mm (OR 1.81, 95% CI, 1.59-2.08). A group of 1469 women (41%)-with tumours without LVSI, tumour size ≤20 mm, and depth of invasion ≤10 mm-had a very low risk of pN+ (2.4%, 95% CI, 1.7-3.3%). CONCLUSION: Early-stage cervical cancer without LVSI, a tumour size ≤20 mm and depth of invasion ≤10 mm, confers a low risk of pN+. Based on an international privacy-preserving analysis, we developed a useful tool to guide the shared decision-making process regarding lymph node dissection.

[Screening, diagnostics, and treatment of cervical cancer in pregnancy].

Cervical cancer is one of the most common cancers in pregnancy. Early diagnosis is of utmost importance for the outcome of the woman and her child. Vaginal bleeding in pregnancy should prompt gynaecological examination, and further diagnostic is needed in women with persistent symptoms. A decision on preservation of the pregnancy in women who are diagnosed with early-stage cervical cancer depends on stage and gestational age, as argued in this review.

Intravascular leiomyomatosis: a continuing diagnostic challenge.

We report the case of a woman in her 60s with intravascular leiomyomatosis. She suffered from numerous non-specific symptoms including weight loss, anaemia and sudden swelling of the left lower extremity. CT imaging showed the presence of an enlarged left ovary and a thrombus extending from the left ovarian venous plexus intruding into the right atrium of the heart. Cancer antigen 125 was 20 U/mL. Pelvic transvaginal ultrasound examination identified two normal ovaries and a mass adjacent to the left ovary. A second opinion on the CT scan was requested at a oncogynaecological multidisciplinary team meeting, where the radiologist of the team identified an intervascular leiomyomatosis. After further investigation, surgical treatment was planned and completed in collaboration with the departments of cardiothoracic and vascular surgery. The patient recovered fully.

The Diagnostic Value of Circulating Cell-Free HPV DNA in Plasma from Cervical Cancer Patients.

Circulating cell-free HPV DNA (ccfHPV DNA) may serve as a marker for cervical cancer. In this study, we used digital droplet PCR (ddPCR) to detect and quantify ccfHPV DNA in plasma from patients with HPV16- or HPV18-associated cervical cancer. Blood samples from 60 patients diagnosed with cervical cancer (FIGO IA1-IVA) at Aarhus or Odense University Hospital (June 2018 to March 2020) were collected prior to treatment, and patients were subdivided into an early stage (n = 30) and a late-stage subgroup (n = 30) according to disease stage. Furthermore, blood samples from eight women with HPV16- or 18-associated premalignant conditions (CIN3), and 15 healthy controls were collected. ddPCR was used to analyze plasma from all participants. ccfHPV DNA was detected in 19 late-stage patients (63.33%), 3 early stage patients (10.00%), and none of the CIN3 patients or controls. Quantitative evaluation showed significant correlations between ccfHPV DNA level and stage, tumor score, and tumor size. Thus, our results indicate that ccfHPV DNA may not be a useful marker for early detection of cervical cancer. However, for patients with advanced stage cervical cancer, ccfHPV DNA level represents a promising tool to establish tumor burden, making it useful for establishing treatment response and monitoring the disease.

Nonepithelial ovarian cancer - the current clinical practice in the Nordic countries. Survey from the surgical subcommittee of the Nordic society of gynecological oncology (NSGO).

BACKGROUND: Nonepithelial ovarian cancer (NEOC) represents a wide variety of rare tumors. They are often diagnosed at an early stage and have a good prognosis compared to epithelial ovarian cancer. In the Nordic countries, the total annual number of patients diagnosed with ovarian cancer, Fallopian tube cancer or primary peritoneal carcinoma (hereafter ovarian cancer) was 2281 in 2014-2018, of which 3-10% were NEOC. International guidelines for diagnosis, treatment and follow-up have been developed. We present the results of a survey, aiming at clarifying current clinical practice in the Nordic countries. MATERIAL AND METHODS: Between 09.2020 and 02.2021 a 33-question electronic survey was distributed to 22 hospitals in Finland, Sweden, Norway, Iceland and Denmark via the Nordic Society of Gynecological Oncology (NSGO) National Representatives. Data were collected in a secure web-based software platform. The questionnaire focused on demographics, diagnosis, treatment and follow-up programs. RESULTS: Twenty-one (95,4%) centers completed the survey. A total of 155 annual new NEOC cases treated in the Nordic countries were reported, corresponding to approximately 7% of all ovarian cancer cases. Most centers measured some or all of the recommended biomarkers routinely. Vaginal ultrasound and computed tomography (CT) were the preferred imaging modalities. The majority of centers conducted multidisciplinary team (MDT) meetings. The primary reported treatment was surgery. In 65% of centers, lymph node dissection was only performed in cases with suspicious lymph nodes. Surveillance was usually offered > four years. DISCUSSION: Despite, the presence of clinical European guidelines, variation in the current clinical practice amongst participating centers adhering to national guidelines was observed. Prospective clinical national research programs are sparse, and an enhanced cooperation in the Nordic countries toward development of a Nordic guideline and database is highly warranted and a prerequisite for future research, preferably in cooperation with the larger international groups.

Evidence of latent HPV infection in older Danish women with a previous history of cervical dysplasia.

INTRODUCTION: Understanding whether human papillomavirus (HPV) may establish latency in the uterine cervix is important. A better understanding of HPV natural history is useful for clinical counseling of women attending screening and to accurately inform health prevention strategies such as screening and HPV vaccination. We evaluated the extent of latent HPV infections in older women with a history of abnormal cytology. MATERIAL AND METHODS: We conducted a cross-sectional study in Aarhus, Denmark, from March 2013 through April 2015. Women were enrolled if they underwent cervical amputation or total hysterectomy because of benign disease. Prior to surgery, women completed a questionnaire and a cervical smear was collected for HPV testing and morphological assessment. For evaluation of latency (i.e., no evidence of active HPV infection, but HPV detected in the tissue), we selected women with a history of abnormal cervical cytology or histology, as these women were considered at increased risk of harboring a latent infection. Cervical tissue underwent extensive HPV testing using the SPF10-DEIA-LipA25 assay. RESULTS: Of 103 women enrolled, 26 were included in this analysis. Median age was 55 years (interquartile range [IQR] 52-65), and most women were postmenopausal and parous. The median number of sexual partners over the lifetime was six (IQR 3-10), and 85% reported no recent new sexual partner. Five women (19.2%) had evidence of active infection at the time of surgery, and 19 underwent latency evaluation. Of these, a latent infection was detected in 11 (57.9%), with HPV16 being the most prevalent type (50%). Nearly 80% (n = 14) of the 18 women with a history of previous low-grade or high-grade cytology with no treatment had an active or latent HPV infection, with latent infections predominating. HPV was detected in two of the six women with a history of high-grade cytology and subsequent excisional treatment, both as latent infections. CONCLUSIONS: HPV can be detected in cervical tissue specimens without any evidence of an active HPV infection, indicative of a latent, immunologically controlled infection. Modeling studies should consider including a latent state in their model when estimating the appropriate age to stop screening and when evaluating the impact of HPV vaccination.

Vaginal melanoma in Denmark from 1980 to 2018: A population-based study based on genetic profile and survival.

OBJECTIVE: To investigate the clinical, pathological, and genetic characteristics of patients with vaginal melanoma in a nationwide setting. MATERIALS/METHODS: All patients diagnosed with vaginal melanoma from 1980 to 2018 were collected by searching the digital archives of the Danish Registry of Pathology (Patobank). Patient specimens were examined, the histological diagnoses were validated, and targeted next-generation sequencing (NGS) of known frequent hot spots in 163 genes was performed. RESULTS: Fifty-two patients were included. The incidence for primary melanoma of the vagina in the Danish population (5.5 million people) was calculated to be 0.24 cases/million/year from 1980 to 2018. For all patients, the median OS was 17.5 months (95% CI: 13.0-24.0), and the 5-year OS was 19.4% (95% CI: 10.9-34.3). We identified frequent mutations in ATRX (7/25 cases) and TP53 (7/25 cases). Mutations found in TP53 were associated with a significant decrease in OS (p = 0.043), whereas mutations in the ATRX gene alone did not show a significant impact on OS (p = 0.3649). Patients who harbored co-mutations in both ATRX and TP53 showed a significant reduction in OS (p = 0.0081), with a median OS of 9.5 months compared to 20 months in those without the co-mutation. CONCLUSIONS: Vaginal melanoma is a rare disease with a poor prognosis presumably due to vague symptoms and the anatomical location of the disease. Co-mutations in ATRX and TP53 and mutations in TP53 alone were associated with a poor prognosis, and these genes are potentially interesting targets for future therapy.

Residual tumor and primary debulking surgery vs interval debulking surgery in stage IV epithelial ovarian cancer.

INTRODUCTION: It is debated whether women with FIGO (International Federation of Gynecology and Obstetrics) Stage IV epithelial ovarian cancer should be offered primary debulking surgery (PDS) or interval debulking surgery (IDS). Furthermore, the impact of complete resection of intra-abdominal disease (R0) despite their extra-abdominal metastases is questioned. The objective of this study was to investigate the impact of intra-abdominal residual tumor, Stage IVA vs IVB, the localization and number of metastases defining Stage IV disease on overall survival (OS) comparing PDS and IDS in FIGO Stage IV epithelial ovarian cancer. MATERIAL AND METHODS: We included 2091 women registered with Stage IIIC-IV ovarian cancer in the Danish Gynecological Cancer Database during 2009-2016. The impact of residual tumor was evaluated using univariate and multivariate analyses. RESULTS: In total, 681 patients had stage IV disease, of whom 26% underwent PDS, 38% IDS, and 36% chemotherapy only. Overall survival for PDS and IDS were similar. Patients achieving R0 at PDS showed a tendency towards a higher OS than patients achieving R0 at IDS, though the difference was non-significant. In women with Stage IVA and IVB disease there was a survival benefit in achieving R0 both when treated with PDS and IDS. Women with Stage IVB disease treated with chemotherapy only had a significantly lower OS than patients achieving R0 at both PDS and IDS. Malignant pleural effusion and having five metastatic sites compared with having one was associated with a poorer OS. CONCLUSIONS: Our study shows similar OS in patients with Stage IV disease treated with IDS compared with PDS. Complete intra-abdominal tumor resection improves the prognosis in both PDS and IDS in Stage IV ovarian cancer. Malignant pleural effusion seems to be a negative prognostic factor and should have more focus in future studies.

SENTIREC - The sentinel node mapping in women with cervical cancer study - Patient-reported early lymphedema and its impact on quality of life.

OBJECTIVE: To evaluate patient-reported incidence and severity of early lymphedema and its impact on quality of life (QoL) after sentinel lymph node (SLN) mapping only and after SLN and pelvic lymphadenectomy (PL) in women undergoing surgery for early-stage cervical cancer. METHODS: In a national prospective multicenter study, we included women with early-stage cervical cancer from March 2017-January 2021 to undergo radical surgery including SLN mapping. Women with tumors >20 mm underwent completion PL. The incidence and severity of early lymphedema and its influence on QoL were evaluated using validated patient-reported outcome measures before surgery and three months postoperative. We investigated changes over time using linear regression. RESULTS: Two hundred of 245 (81.6%) included women completed questionnaires at baseline and three months postoperatively. The incidence of early lymphedema was 5.6% (95% CI 2.1-11.8%) and 32.3% (95% CI 22.9-42.7%) in women who underwent SLN mapping only and SLN + PL, respectively. Lymphedema symptoms in the legs, genitals, and groins increased in both groups postoperatively but three times more in women who underwent PL. Lymphedema symptoms after SLN + PL significantly impaired physical performance (p = 0.001) and appearance (p = 0.007). Reporting lymphedema was significantly associated with impaired body image, physical-, role-, and social functioning, and a high level of fatigue. CONCLUSIONS: SLN mapping alone carries a low risk of lymphedema in women undergoing surgery for early-stage cervical cancer. In contrast, completion PL is associated with a high incidence of early lymphedema. Reporting lymphedema is associated with significant impairment of several physical, psychological, and social aspects of QoL.

From FIGO-2009 to FIGO-2018 in women with early-stage cervical cancer; Does the revised staging reflect risk groups?

OBJECTIVES: We aimed to evaluate if the revised staging according to FIGO-2018 in early-stage cervical cancer correctly predicts the risk for nodal metastases. METHODS: We reallocated 245 women with early-stage cervical cancer from FIGO-2009 to FIGO-2018 stages using data from a national, prospective cohort study on sentinel lymph node (SLN) mapping. We used univariate and multivariate binary regression models to investigate the association between FIGO-2018 stages, tumor characteristics, and nodal metastases. RESULTS: Stage migration occurred in 54.7% (134/245) (95% CI 48.2-61.0), due to tumor size or depth of invasion (71.6%, 96/134) and nodal metastases (28.4%, 38/134). Imaging preoperatively upstaged 7.3% (18/245); seven had nodal metastatic disease on final pathology. Upstaging occurred in 49.8% (122/245) (95% CI 43.4-56.2%) and downstaging to FIGO-2018 IA stages in 4.9% (12/245) (95% CI 2.6-8.4). The tumor size ranged from 3.0-19.0 mm in women with FIGO-2018 IA tumor characteristics, and none of the 14 women had nodal metastases. In multivariate analysis, risk factors significantly associated with nodal metastases were FIGO-2018 ≥ IB2 (RR 5.01, 95% CI 2.30-10.93, p < 0.001), proportionate depth of invasion >2/3 (RR 1.88, 95% CI 1.05-3.35, p = 0.033), and lymphovascular space invasion (RR 5.56, 95% CI 2.92-10.62, p < 0.001). CONCLUSIONS: The FIGO-2018 revised staging system causes stage migration for a large proportion of women with early-stage cervical cancer. Women who were downstaged to FIGO-2018 IA stages did not have nodal metastatic disease. The attention on depth of invasion rather than horizontal dimension seems to correctly reflect the risk of nodal metastases.

Sentinel lymph node mapping in early-stage cervical cancer - A national prospective multicenter study (SENTIREC trial).

OBJECTIVES: Sentinel lymph node (SLN) mapping may replace staging radical pelvic lymphadenectomy in women with early-stage cervical cancer. In a national multicenter setting, we evaluated SLN mapping in women with early-stage cervical cancer and investigated the accuracy of SLN mapping and FDG-PET/CT in tumors >20 mm. METHODS: We prospectively included women with early-stage cervical cancer from March 2017-January 2021 to undergo SLN mapping. Women with tumors >20 mm underwent completion pelvic lymphadenectomy and removal of FDG-PET/CT positive nodes. We determined SLN detection rates, incidence of nodal disease, sensitivity and negative predictive value (NPV) of SLN mapping, and the sensitivity, specificity, NPV, and positive predictive value (PPV) of FDG-PET/CT. RESULTS: We included 245 women, and 38 (15.5%) had nodal metastasis. The SLN detection rate was 96.3% (236/245), with 82.0% (201/245) bilateral detection. In a stratified analysis of 103 women with tumors >20 mm, 27 (26.2%) had nodal metastases. The sensitivity of SLN mapping adhering to the algorithm was 96.3% (95% CI 81.0-99.9%) and the NPV 98.7% (95% CI 93.0-100%). For FDG-PET/CT imaging the sensitivity was 14.8% (95% CI 4.2-33.7%), the specificity 85.5% (95% CI 75.6-92.5%), the NPV 73.9% (95% CI 63.4-82.7%), and the PPV 26.7% (95% CI 7.8-55.1%). CONCLUSIONS: SLN mapping seems to be an adequate staging procedure in early-stage cervical cancer tumors ≤20 mm. In tumors >20 mm, SLN mapping is highly sensitive but demands full adherence to the SLN algorithm. We recommend completion pelvic lymphadenectomy in tumors >20 mm until the oncological safety is established. FDG-PET/CT for nodal staging of women with early-stage cervical cancer seems limited.

Sentinel lymph node mapping for endometrial and cervical cancer in Denmark.

INTRODUCTION: This was a surgical pilot study to systematically introduce the technique of sentinel lymph node (SLN) mapping in women with early-stage stage cervical cancer (CC) and endometrial cancer (EC) in Denmark. The study aimed to facilitate structured surgical training to ensure surgeon proficiency in SLN mapping. The study precedes two national prospective studies on the oncological safety and correct patient selection for SLN mapping in CC and EC. METHODS: The study was conducted at four gynaecological cancer centres at Odense and Aarhus University Hospital, Rigshospitalet and Herlev Hospital, between September 2016 and August 2019. All centres went through a protocolled introduction to the surgical technique, pelvic lymphatic drainage, pathological ultra-staging and data entry. A criterion of a total (uni- and bilateral) SLN detection of > 80%, based on 30 SLN mappings was set. RESULTS: The four centres performed 140 (range: 30-46) procedures. The total SLN detection rate was 91.3% with bilateral SLN detection in 68.8% and unilateral SLN detection in 22.5% of cases. The cumulated total SLN detection rate at three centres was above the pre-set 80% criterion from the beginning of inclusion, whereas one centre reached the criterion after 20 procedures. CONCLUSIONS: In this study, all centres demonstrated international-level SLN detection rates within 30 procedures. Hence, all centres met the study criterion regarding surgeon proficiency and were eligible for the national studies. FUNDING: Eva and Henry Frænkels Fond, Frimodt-Heineke Fonden, Kong Christian X Fond. TRIAL REGISTRATION: The study was approved by the Danish Data Protection Agency (R. no.15/52037). The SENTIREC studies including this pilot study are registered with clinicaltrials.gov (NCT02825355 and NCT02820506).

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.

Detection of high-risk human papillomavirus DNA in tissue from primary cervical cancer tumor, pelvic lymph nodes and recurrent disease.

OBJECTIVES: The present study investigated Human Papillomavirus (HPV) DNA genotyping in primary tumor, pelvic lymph nodes (PLN) and recurrence in early-stage cervical cancer patients. METHODS: We conducted a hospital-based case-control study. From 2003 to 2015, 282 patients underwent surgery for cervical cancer in the Department of Gynecology, Aarhus University Hospital, Denmark. Twenty-nine recurrent cases were identified. HPV DNA genotyping was performed on formalin-fixed, paraffin-embedded tissue specimens from the primary tumor, PLN, and recurrent disease. RESULTS: In the primary tumor, HPV DNA was detectable in 18(72%) of 25 tissue specimens from recurrent cases and in 15(83%) of 18 controls. HPV DNA-positive PLN was significantly associated with recurrence, 83%(95%CI: 52-98%), compared to patients with HPV-negative PLN, 38%(95%CI: 18-62%)(p < 0.05). HPV DNA genotyping was positive in eight of 12(67%) patients with recurrent disease. The genotype was identical in all three tissues types. The positive predictive value for recurrence was the same for detection of HPV-DNA and metastases in the PLN, with reasonable sensitivity. The negative predictive value for recurrence, however, was best for HPV-DNA, 62%(95%CI: 38-98%). CONCLUSIONS: In conclusion, our data suggest that the presence of HPV in pelvic lymph nodes is associated with an increased risk of recurrence.

Cervical cancer staging, pretreatment planning, and surgical treatment in the Nordic countries-Survey from the Surgical Subcommittee of the Nordic Society of Gynecological Oncology.

INTRODUCTION: Women with cervical cancer in the Nordic countries are increasingly undergoing pretreatment imaging by ultrasound, magnetic resonance imaging (MRI), positron emission tomography-computed tomography (PET-CT) or computed tomography, or sentinel lymph node procedure. The present survey reports the influence of pretreatment imaging findings on the recorded clinical International Federation of Gynecology and Obstetrics (FIGO) stage in Nordic countries and its impact on treatment planning and preferred surgical approach in cervical cancer. MATERIAL AND METHODS: The Nordic Society of Gynecological Oncology Surgical Subcommittee developed a questionnaire-based survey that was conducted from 1 January to 31 March 2017. All the 22 Nordic Gynecological Oncology Centers (Denmark 5, Finland 5, Iceland 1, Norway 4, and Sweden 7) were invited to participate. RESULTS: The questionnaires were returned by 19 of 22 (86.3%) centers. The median number (range) of women with cervical cancer treated at each center annually was 32 (15-120). In 58% (11/19) of the centers, imaging findings were reported to influence the clinical staging. MRI in combination with PET-CT was the preferred imaging method and the results influenced treatment planning. Robotic-assisted radical hysterectomy was the preferred surgical method in 72% (13/18) of the centers. Sentinel lymph node procedure was not routinely implemented in the majority of the Nordic centers. CONCLUSION: More than half of the Nordic Gynecological Oncology Centers already report a clinical FIGO stage influenced by pretreatment imaging findings. The trend in preferred treatment is robotic-assisted radical hysterectomy and the sentinel lymph node procedure is gradually being introduced.

Risk of recurrence, prognosis, and follow-up for Danish women with cervical cancer in 2005-2013: A national cohort study.

BACKGROUND: In developed countries, women attend follow-up after treatment for cervical cancer to detect recurrence. The aim of this study was to describe the Danish population of women with early-stage cervical cancer at risk for recurrence and death due to recurrence. METHODS: Data were extracted from 3 nationwide databases to find women diagnosed with stage 1A1 to 1B1 cervical cancer in 2005-2013. Recurrences were determined from data on oncological or surgical treatment more than 3 months after the initial diagnosis and were cross-checked with patient journals. RESULTS: In all, 1523 patients were diagnosed with stage 1A1 to 1B1 cervical cancer. Eighty women experienced recurrences: 8 at International Federation of Gynecology and Obstetrics (FIGO) stage 1A1, 0 at FIGO stage 1A2, and 72 at FIGO stage 1B1. The 5-year recurrence rate was 6.4%; 67.5% of the women had symptomatic recurrences, and 28.8% had asymptomatic recurrences. At significantly greater risk for recurrence were women at stage 1B1, regardless of their lymph node (LN) status at diagnosis (hazard ratio with a positive LN, 5.10; 95% confidence interval [CI], 1.65-15.76; P = .0047; hazard ratio with a negative LN, 3.14; 95% CI, 1.25-7.93; P = .0153; hazard ratio with LN data missing, 6.33; 95% CI, 1.80-22.26; P = .004), women older than 50 years (hazard ratio, 1.81; 95% CI, 1.12-2.94; P = .0158), and women with lymphatic and lymphovascular space invasion (LVSI; hazard ratio, 1.92; 95% CI, 1.11-3.30; P = .0188). In a multivariate analysis, significantly inferior survival was found after recurrence for patients with lymphatic LVSI (hazard ratio, 2.23; 95% CI, 1.04-4.80; P = .0401), a symptomatic diagnosis of recurrence (hazard ratio, 2.52; 95% CI, 1.08-5.90; P = .0332), and multiple sites of recurrence (hazard ratio, 2.72; 95% CI, 1.32-5.61; P = .0066). CONCLUSIONS: This study has identified a group of women at FIGO stage 1A1 in no need of specialized, hospital-based follow-up. Many of the recurrences at FIGO stage 1B1 are asymptomatic, and this may show a need for follow-up in this group. Further prospective investigation is needed. Cancer 2018;124:943-51. © 2017 American Cancer Society.

[Screening for cervical cancer in women older than 65 years will probably reduce the incidence and mortality]. / Screening for cervixcancer hos kvinder over 65 år vilformentlig nedsætte incidensen og mortaliteten

The age-specific cervical cancer incidence in Denmark is bimodal with peaks at ages 35-40 years and 75 years. Yet, Danish women ≥ 65 years are not offered screening for cervical cancer. Screening women beyond the age of 65 years may reduce cervical cancer incidence as well as mortality, and seems to be cost-effective. Older women may benefit more from human papillomavirus screening rather than by cytology. Thus, more research on cervical cancer screening in older women is warranted.

Addressing challenges in future surveillance after surgery for early-stage cervical cancer.

OBJECTIVE: This study examines surveillance after early-stage cervical cancer surgery. Since the 1980s, the value of surveillance has been discussed continuously. The main question explored is whether surveillance serves the purpose of ensuring early diagnosis of recurrence. MATERIALS AND METHODS: A retrospective cohort study included 389 women with cervical cancer who underwent surgery as the primary treatment modality at the Department of Obstetrics and Gynecology, Aarhus University Hospital, Denmark, from 1996 to 2011. We used data from patient files and the Danish National Pathology Data Bank. The cumulative risk was estimated by the Kaplan-Meier method and tested by the log-rank test. RESULTS: Forty-three women (11%) had recurrence. Only 27% of the recurrent cases were diagnosed at a scheduled surveillance appointment, but they were often asymptomatic and seemed to have a better outcome after treatment compared with the recurrent cases diagnosed at self-referral.The 5-year survival was overall 91.3%, recurrence-free survival was 96%, and cancer-specific survival was 54%. The median recurrence-free interval was 23 months (range, 4-144) for the symptomatic patients and 14 months (range, 4-48) for the asymptomatic patients. The median survival after recurrence was 12 months (range, 2-132) for the symptomatic patients and 156 months (range, 40-180) for the asymptomatic patients. CONCLUSIONS: At the moment, neither the value of surveillance nor the significance of self-referral related to survival after recurrence is known. In this study, those who are diagnosed with recurrence before symptom onset seem to fare better in terms of 5-year survival than those who are diagnosed after self-referral because of symptoms.

Cell-mediated immune response: a clinical review of the therapeutic potential of human papillomavirus vaccination.

OBJECTIVE: This clinical review aims to assess the efficacy of human papillomavirus 16/18 (HPV16/18) vaccination on the cell-mediated immune response in women with existing cervical intraepithelial neoplasia or cervical cancer induced by HPV16 or HPV18. DATA SOURCES AND STUDY SELECTION: A focused and thorough literature search conducted in five different databases found 996 publications. Six relevant articles were chosen for further review. In total, 154 patients (>18 years of age) were enrolled in prospective study trials with 3-15 months of follow up. The vaccine applications were administered two to four times. The vaccines contained different combinations of HPV16 and HPV18 and early proteins, E6 and E7. The primary outcome was the cell-mediated immune response. Correlation to clinical outcome (histopathology) and human leukocyte antigen genes were secondary endpoints. RESULTS: All vaccines triggered a detectable cell-mediated immune response, some of which were statistically significant. Correlations between immunological response and clinical outcome (histopathology) were not significant, so neoplasms may not be susceptible to vaccine-generated cytotoxic T cells (CD8(+)). CONCLUSIONS: Prophylactic HPV vaccines have been introduced to reduce the incidence of cervical cancer in young women. Women already infected with HPV could benefit from a therapeutic HPV vaccination. Hence, it is important to continue the development of therapeutic HPV vaccines to lower the rate of HPV-associated malignancies and crucial to evaluate vaccine efficacy clinically. This clinical review represents an attempt to elucidate the theories supporting the development of an HPV vaccine with a therapeutic effect on human papillomavirus-induced malignancies of the cervix.