Diagnostic accuracy of MRI, CT, and [18F]FDG-PET-CT in detecting lymph node metastases in clinically early-stage cervical cancer - a nationwide Dutch cohort study.

OBJECTIVES: Imaging is increasingly used to assess lymph node involvement in clinically early-stage cervical cancer. This retrospective study aimed to evaluate the diagnostic accuracy of MRI, CT, and [18F]FDG-PET-CT. METHODS: Women with International Federation of Gynaecology and Obstetrics (FIGO) 2009 stage IA2-IIA cervical cancer and pretreatment imaging between 2009 and 2017 were selected from the Netherlands Cancer Registry. Patient-based and region-based (i.e. pelvic and common iliac) nodal status was extracted from radiology reports. Pathology results were considered the reference standard for calculating accuracy indices. Multiple imputation was used for missing pathology to limit verification bias risk. RESULTS: Nodal assessment was performed in 1676 patients with MRI, 926 with CT, and 379 with [18F]FDG-PET-CT, with suspicious nodes detected in 17%, 16%, and 48%, respectively. [18F]FDG-PET-CT was used to confirm MRI/CT results in 95% of patients. Pathology results were imputed for 30% of patients. [18F]FDG-PET-CT outperformed MRI and CT in detecting patient-based nodal metastases with sensitivities of 80%, 48%, and 40%, and AUCs of 0.814, 0.706, and 0.667, respectively, but not in specificity: 79%, 92%, and 92%. Region-based analyses showed similar indices in the pelvic region, but worse performance in the common iliac region with AUCs of 0.575, 0.554, and 0.517, respectively. CONCLUSIONS: [18F]FDG-PET-CT outperformed MRI and CT in detecting nodal metastases, which may be related to its use as a verification modality. However, MRI and CT had the highest specificity. As MRI is generally performed routinely to assess local and regional spread of cervical cancer, [18F]FDG-PET-CT can be used to confirm suspicious nodes. CRITICAL RELEVANCE STATEMENT: Accurate assessment of the nodal status in clinically early-stage cervical cancer is essential for tumour staging, treatment decision making and prognosis. KEY POINTS: • The accuracy of MRI, CT or [18F]FDG-PET-CT for nodal staging in early cervical cancer is a subject of discussion. • Overall, [18F]FDG-PET-CT outperformed MRI, followed by CT, when used as a verification modality. • Staging with MRI and the addition of [18F]FDG-PET-CT to verify high-risk cases seems to be a good approach.

Optimising follow-up strategy based on cytology and human papillomavirus after fertility-sparing surgery for early stage cervical cancer: a nationwide, population-based, retrospective cohort study.

BACKGROUND: The optimal follow-up strategy to detect recurrence after fertility-sparing surgery for early stage cervical cancer is unknown. Tailored surveillance based on individual risks could contribute to improved efficiency and, subsequently, reduce costs in health care. The aim of this study was to establish the predictive value of cervical cytology and high-risk human papillomavirus (HPV) testing to detect recurrent cervical intraepithelial neoplasia grade 2 or worse (CIN2+; including recurrent cervical cancer) after fertility-sparing surgery. METHODS: In this nationwide, population-based, retrospective cohort study, we used data from the Netherlands Cancer Registry and the Dutch Nationwide Pathology Databank. All patients aged 18-40 years with cervical cancer of any histology who received fertility-sparing surgery (ie, large loop excision of the transformation zone, conisation, or trachelectomy) between Jan 1, 2000, and Dec 31, 2020, were included. Pathology data from diagnosis, treatment, and during follow-up were analysed. The primary and secondary outcomes were the cumulative incidence of recurrent CIN2+ and recurrence-free survival, overall and stratified by results for cytology and high-risk HPV. FINDINGS: 1548 patients were identified, of whom 1462 met the inclusion criteria. Of these included patients, 19 568 pathology reports were available. The median age at diagnosis was 31 years (IQR 30-35). After a median follow-up of 6·1 years (IQR 3·3-10·8), recurrent CIN2+ was diagnosed in 128 patients (cumulative incidence 15·0%, 95% CI 11·5-18·2), including 52 patients (cumulative incidence 5·4%, 95% CI 3·7-7·0) with recurrent cervical cancer. The overall 10-year recurrence-free survival for CIN2+ was 89·3% (95% CI 87·4-91·3). By cytology at first follow-up visit within 12 months after fertility-sparing surgery, 10-year recurrence-free survival for CIN2+ was 92·1% (90·2-94·1) in patients with normal cytology, 84·6% (77·4-92·3) in those with low-grade cytology, and 43·1% (26·4-70·2) in those with high-grade cytology. By high-risk HPV status at first follow-up visit within 12 months after surgery, 10-year recurrence-free survival for CIN2+ was 91·1% (85·3-97·3) in patients who were negative for high-risk HPV and 73·6% (58·4-92·8) in those who were positive for high-risk HPV. Cumulative incidence of recurrent CIN2+ within 6 months after any follow-up visit (6-24 months) in patients negative for high-risk HPV with normal or low-grade cytology was 0·0-0·7% and with high-grade cytology was 0·0-33·3%. Cumulative incidence of recurrence in patients positive for high-risk HPV with normal or low-grade cytology were 0·0-15·4% and with high-grade cytology were 50·0-100·0%. None of the patients who were negative for high-risk HPV without high-grade cytology, at 6 months and 12 months, developed recurrence. INTERPRETATION: Patients who are negative for high-risk HPV with normal or low-grade cytology at 6-24 months after fertility-sparing surgery, could be offered a prolonged follow-up interval of 6 months. This group comprises 80% of all patients receiving fertility-sparing surgery. An interval of 12 months seems to be safe after two consecutive negative tests for high-risk HPV with an absence of high-grade cytology, which accounts for nearly 75% of all patients who receive fertility-sparing surgery. FUNDING: KWF Dutch Cancer Society.

Sentinel lymph node procedure in early-stage vulvar cancer: Correlation of lymphoscintigraphy with surgical outcome and groin recurrence.

INTRODUCTION: In early-stage vulvar squamous cell carcinoma (VSCC) a sentinel lymph node (SLN) procedure is regarded successful if at least one SLN is removed with minimal residual radioactivity. An inguinofemoral lymphadenectomy is considered if not all SLNs visualized on lymphoscintigraphy can be found, with subsequent increased morbidity. We correlated lymphoscintigraphy findings with surgical outcome and groin recurrence with focus on number of SLNs found. METHODS: This study concerns a retrospective cohort of 171 women treated for early-stage VSCC who underwent a SLN procedure between 2000 and 2020. The risk of groin recurrence was compared after either a successful or complete SLN procedure, i.e. removal of all SLNs that were visualized on lymphoscintigraphy. RESULTS: In 13 (7.6%) groins of 171 patients SLN visualization on lymphoscintigraphy failed. In 230 of the 246 (93.5%) groins in which a SLN was visualized, at least one SLN was found during surgery. In 224 of the 246 (91.1%) groins the SLN procedure was regarded either successful (n = 14) or complete (n = 210). An isolated groin recurrence was documented in 5 out of 192 (2.6%, 95%-CI; 0.34 to 4.9) SLN-negative groins after a median follow-up of 47.0 months. All recurrences were noted in the complete SLN group (5/180 groins). The difference with the successful SLN group (0/12 groins) was not significant. CONCLUSION: Risk of groin recurrence was 2.6% after SLN negative biopsy in early-stage VSCC. The risk appeared not increased if at least one SLN was found with minimal residual radioactivity, in case more SLNs were visualized on lymphoscintigraphy.

Investigating feasibility of 2021 WHO protocol for cervical cancer screening in underscreened populations: PREvention and SCReening Innovation Project Toward Elimination of Cervical Cancer (PRESCRIP-TEC).

BACKGROUND: High-risk human papillomavirus (hrHPV) testing has been recommended by the World Health Organization as the primary screening test in cervical screening programs. The option of self-sampling for this screening method can potentially increase women's participation. Designing screening programs to implement this method among underscreened populations will require contextualized evidence. METHODS: PREvention and SCReening Innovation Project Toward Elimination of Cervical Cancer (PRESCRIP-TEC) will use a multi-method approach to investigate the feasibility of implementing a cervical cancer screening strategy with hrHPV self-testing as the primary screening test in Bangladesh, India, Slovak Republic and Uganda. The primary outcomes of study include uptake and coverage of the screening program and adherence to follow-up. These outcomes will be evaluated through a pre-post quasi-experimental study design. Secondary objectives of the study include the analysis of client-related factors and health system factors related to cervical cancer screening, a validation study of an artificial intelligence decision support system and an economic evaluation of the screening strategy. DISCUSSION: PRESCRIP-TEC aims to provide evidence regarding hrHPV self-testing and the World Health Organization's recommendations for cervical cancer screening in a variety of settings, targeting vulnerable groups. The main quantitative findings of the project related to the impact on uptake and coverage of screening will be complemented by qualitative analyses of various determinants of successful implementation of screening. The study will also provide decision-makers with insights into economic aspects of implementing hrHPV self-testing, as well as evaluate the feasibility of using artificial intelligence for task-shifting in visual inspection with acetic acid. TRIAL REGISTRATION: ClinicalTrials.gov, NCT05234112 . Registered 10 February 2022.

Treatment of bulky lymph nodes in locally advanced cervical cancer: boosting versus debulking.

OBJECTIVE: Treatment strategies for bulky lymph nodes in patients with locally advanced cervical cancer scheduled for definitive chemoradiation include nodal boosting with radiotherapy, surgical debulking, or both. The aim of this retrospective cohort study was to compare survival and toxicity in patients receiving these treatments and to compare them with a group that received neither form of treatment. METHODS: Women diagnosed between January 2009 and January 2017 with International Federation of Gynecology and Obstetrics (FIGO) 2009 stage IB2, IIA2-IVA cervical cancer with lymph nodes ≥1.5 cm without upper limit on pretreatment imaging and treated with definitive chemoradiation were selected from the Netherlands Cancer Registry. Patients were categorized by intention-to-treat strategy: boosting, debulking, or neither treatment, with subgroup analysis for patients receiving both treatments, that is, debulking with boosting. Overall and relapse-free survival outcomes were compared by Kaplan-Meier and Cox regression analyses and toxicity by logistic regression analysis. RESULTS: Of 190 patients, 101 (53%) received only nodal boosting, 31 (16%) debulking alone, 29 (15%) debulking combined with boosting, and 29 (15%) received neither treatment. The 5 year overall and relapse-free survival for the treatment groups were 58%, 45% and 45% (p=0.19), and 47%, 44% and 46% (p=0.87), respectively. Multivariable Cox regression analyses demonstrated no differences in overall and relapse-free survival. Combination of debulking with boosting was associated with decreased overall and relapse-free survival compared with debulking alone (HR 2.47, 95% CI 1.22 to 5.00; and HR 2.37, 95% CI 1.14 to 4.93). Nodal boosting was independently associated with a decreased toxicity risk compared with debulking strategy (OR 0.37, 95% CI 0.16 to 0.83). CONCLUSIONS: This study showed no survival benefit from either nodal boosting or debulking strategy in patients with suspicious bulky nodes. Nodal boosting might, however, be associated with less toxicity. Dual treatment with debulking and boosting showed a worse survival outcome because this group probably represents patients with poor prognostic factors.

Near-infrared fluorescence imaging compared to standard sentinel lymph node detection with blue dye in patients with vulvar cancer - a randomized controlled trial.

OBJECTIVE: The aim of this study was to assess the superiority of ICG-99mTc-nanocolloid for the intraoperative visual detection of sentinel lymph nodes (SLNs) in vulvar squamous cell carcinoma (VSCC) patients compared to standard SLN detection using 99mTc-nanocolloid with blue dye. METHODS: In this multicenter, randomized controlled trial, VSCC patients underwent either the standard SLN procedure or with the hybrid tracer ICG-99mTc-nanocolloid. The primary endpoint was the percentage of fluorescent SLNs compared to blue SLNs. Secondary endpoints were successful SLN procedures, surgical outcomes and postoperative complications. RESULTS: Forty-eight patients were randomized to the standard (n = 24) or fluorescence imaging group (n = 24) using ICG-99mTc-nanocolloid. The percentage of blue SLNs was 65.3% compared to 92.5% fluorescent SLNs (p < 0.001). A successful SLN procedure was obtained in 92.1% of the groins in the standard group and 97.2% of the groins in the fluorescence imaging group (p = 0.33). Groups did not differ in surgical outcome, although more short-term postoperative complications were documented in the standard group (p = 0.041). CONCLUSIONS: Intraoperative visual detection of SLNs in patients with VSCC using ICG-99mTc-nanocolloid was superior compared to 99mTc-nanocolloid and blue dye. The rate of successful SLN procedures between both groups was not significantly different. Fluorescence imaging has potential to be used routinely in the SLN procedure in VSCC patients to facilitate the search by direct visualization. CLINICAL TRIAL REGISTRATION: Netherlands Trial Register (Trial ID NL7443).

Survival of patients with early-stage cervical cancer after abdominal or laparoscopic radical hysterectomy: a nationwide cohort study and literature review.

AIM: Recently, the safety of laparoscopic radical hysterectomy (LRH) has been called into question in early-stage cervical cancer. This study aimed to evaluate overall survival (OS) and disease-free survival (DFS) in patients treated with abdominal radical hysterectomy (ARH) and LRH for early-stage cervical cancer and to provide a literature review. METHODS: Patients diagnosed between 2010 and 2017 with International Federation of Gynaecology and Obstetrics (2009) stage IA2 with lymphovascular space invasion, IB1 and IIA1, were identified from the Netherlands Cancer Registry. Cox regression with propensity score, based on inverse probability treatment weighting, was applied to examine the effect of surgical approach on 5-year survival and calculate hazard ratios (HR) and 95% confidence intervals (CIs). Literature review included observational studies with (i) analysis on tumours ≤4 cm (ii) median follow-up ≥30 months (iii) ≥5 events per predictor parameter in multivariable analysis or a propensity score. RESULTS: Of the 1109 patients, LRH was performed in 33%. Higher mortality (9.4% vs. 4.6%) and recurrence (13.1% vs. 7.3%) were observed in ARH than LRH. However, adjusted analyses showed similar DFS (89.4% vs. 90.2%), HR 0.92 [95% CI: 0.52-1.60]) and OS (95.2% vs. 95.5%), HR 0.94 [95% CI: 0.43-2.04]). Analyses on tumour size (<2/≥2 cm) also gave similar survival rates. Review of nine studies showed no distinct advantage of ARH, especially in tumours <2 cm. CONCLUSION: After adjustment, our retrospective study showed equal oncological outcomes between ARH and LRH for early-stage cervical cancer - also in tumours <2 cm. This is in correspondence with results from our literature review.

Folate receptor-α targeted near-infrared fluorescence imaging in high-risk endometrial cancer patients: a tissue microarray and clinical feasibility study.

OBJECTIVE: Detection and resection of all malignant lesions is pivotal in staging and cytoreductive surgery (CRS) of endometrial cancer (EC). Intraoperative EC detection could be enhanced using OTL-38, a fluorescent-labelled folate receptor-α (FRα) targeted imaging agent. The objectives of this study were to investigate which subgroups of high-risk EC patients express FRα and assess feasibility of intraoperative EC detection using OTL-38. RESULTS: FRα expression on TMA was significantly correlated with tumor type (p < 0.01). Eighty-two percent of serous and clear cell carcinomas showed FRα expression. Four patients were enrolled in the clinical study. Using fluorescence imaging all omental (n = 3) and lymph node (LN) metastases (n = 16) could be clearly identified, including one otherwise undetected omental metastasis. However, false-positive fluorescence was identified in 17/50 non-metastatic LNs, caused by OTL-38 targeting of FRß, expressed by tumor-associated activated macrophages. CONCLUSIONS: This study describes high FRα expression in serous and clear cell EC and demonstrates the first experience of intraoperative FRα-targeted tumor detection in patients with these subtypes of EC. Although all metastases could be clearly identified using OTL-38, the role of tumor-associated macrophages should be further evaluated. METHODS: Immunohistochemical (IHC) staining of FRα expression was performed on tissue micro arrays (TMA) of 116 patients with high-risk EC features. Patients with either serous or clear cell EC, planned for staging or CRS, were eligible for inclusion in the clinical study and received an intravenous dose of 0.0125 mg/kg OTL-38, 2-3 hours prior to surgery. Resected lesions, identified by standard-of-care and/or fluorescence imaging, were histopathologically assessed for FRα and tumor status.

L1 cell adhesion molecule (L1CAM) is a strong predictor for locoregional recurrences in cervical cancer.

BACKGROUND: L1 cell adhesion molecule (L1CAM) has been shown to be a prognostic marker in various cancer types, and has been suggested to play a role in epithelial mesenchymal transition (EMT). Here, we determined the prognostic significance of L1CAM in cervical cancer and its association with vimentin expression on tumor cells, indicative of EMT. METHODS: Formalin-fixed, paraffin-embedded primary tumor samples from 372 cervical cancer patients were collected for immunohistochemical analysis of L1CAM expression. In 109 FFPE specimens, the percentage of vimentin expressing tumor cells was determined by flow cytometry. RESULTS: Positive L1CAM expression (≥10% of tumor cells) was associated with disease-free survival, validated using RNAseq TCGA data. L1CAM expression was independently associated with locoregional recurrence-free survival (hazard ratio 2.62, 95% CI 1.33 - 5.17, P = 0.006), and strongly associated with percentage of vimentin expressing tumor cells (P = 0.003). Expression of both L1CAM and vimentin indicated a subgroup with the highest risk of recurrence (hazard ratio 3.15, 95% CI 1.25 - 7.92, P = 0.015). CONCLUSION: L1CAM might be a promising new prognostic marker for locoregional recurrences in cervical cancer, and its association with vimentin expression suggests that L1CAM might affect tumor aggressiveness, possibly through EMT.

[Crisis in human resources for health: millennium development goals for maternal and child health threatened]. / Tekort aan gezondheidswerkers in Afrika: millenniumdoelstellingen voor moeder- en kindzorg in gevaar.

International migration of health care workers from low-income countries to the West has increased considerably in recent years, thereby jeopardizing the achievements of The Millennium Development Goals, especially number 4 (reduction of child mortality) and 5 (improvement of maternal health).This migration, as well as the HIV/AIDS epidemic, lack of training of health care personnel and poverty, are mainly responsible for this health care personnel deficit. It is essential that awareness be raised amongst donors and local governments so that staffing increases, and that infection prevention measures be in place for their health care personnel. Western countries should conduct a more ethical recruitment of health care workers, otherwise a new millennium development goal will have to be created: to reduce the human resources for health crisis.