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Women treated for CIN2/3 remain at increased risk of recurrent CIN and cervical cancer, and therefore posttreatment surveillance is recommended. This post hoc analysis evaluates the potential of methylation markers ASCL1/LHX8 and FAM19A4/miR124‐2 for posttreatment detection of recurrent CIN2/3. Cervical scrapes taken at 6 and 12 months posttreatment of 364 women treated for CIN2/3 were tested for methylation of ASCL1/LHX8 and FAM19A4/miR124‐2 using quantitative multiplex methylation‐specific PCR. Performance of the methylation tests were calculated and compared with the performance of HPV and/or cytology. Methylation levels of recurrent CIN were compared between women with a persistent HPV infection, and women with an incident HPV infection or without HPV infection. Recurrent CIN2/3 was detected in 42 women (11.5%), including 28 women with CIN2 and 14 with CIN3. ASCL1/LHX8 tested positive in 13/14 (92.9%) of recurrent CIN3 and 13/27 (48.1%) of recurrent CIN2. FAM19A4/miR124‐2 tested positive in 14/14 (100%) of recurrent CIN3 and 10/27 (37.0%) of recurrent CIN2. Combined HPV and/or methylation testing showed similar positivity rates as HPV and/or cytology. The CIN2/3 risk at 12 months posttreatment was 30.8% after a positive ASCL1/LHX8 result at 6 months posttreatment. Methylation levels of CIN2/3 in women with a persistent HPV infection were significantly higher compared with women with an incident or no HPV infection. In conclusion, posttreatment monitoring by methylation analysis of ASCL1/LHX8 and FAM19A4/miR124‐2 showed a good performance for the detection of recurrent CIN. DNA methylation testing can help to identify women with recurrent CIN that require re‐treatment. [ABSTRACT FROM AUTHOR]

Recently, the European Society of Gynaecological Oncology (ESGO) presented fifteen quality indicators (QIs) with the aim to improve quality of surgical treatment for cervical cancer. In this study, we analyzed compliance with these QIs in a large referral center in the Netherlands. A critical analysis of the QIs that deviated from the targets was performed. Data of all 402 patients, who were surgically treated for cervical cancer with International Federation of Gynaecology and Obstetrics (FIGO) 2009 stage IA-IIA at the Amsterdam University Medical Center from 2007-2016, were retrospectivly analyzed with regard to adherence to the ESGO QIs. Targets set for three out of 15 ESGO QIs were not met. A pre-operative Magnetic Resonance Imaging (MRI) was performed in 92% of patients (target 100%). The percentage of upstaging of clinical stage into a higher pathological stage after surgery was 17.2% (target <10%). The third target that was not met was the minimally required elements in the pathology report. Parametrial length measured in two dimensions, histological grade and extra-nodal extension of lymph node metastasis were reported in respectively 0%, 32% and 42%, whereas the target was =90%. In contrast to the three QI targets that were not met, performance with regard to two out of 15 QI was far better than the targets set. This included recurrence rate at 2 years and the percentage of adjuvant (chemo)radiotherapy in (p)T1b1N0. QIs are important to evaluate care. They should be clearly described to ensure they are correctly interpreted. QIs and their targets should be based on solid evidence to ensure that reaching the target results in improvement of quality of care. Although the three QI targets that were not reached in our center are subject to criticism, they are still useful for prospective data collection and quality evaluation. [ABSTRACT FROM AUTHOR]

Objective: In the 2018 FIGO staging system, cervical cancers with ≥5 mm depth of invasion (DOI) and a diameter of >7 mm, first classified as stage IB, are classified as stage IA. In this group, it is unclear what the risk of lymph node metastasis (LNM) is. This retrospective cohort study aims to determine the incidence of LNM and to study the association between disease-related characteristics and LNM. Methods: Women diagnosed with FIGO 2009 IB cervical cancer, with ≤5 mm DOI and a diameter >7 mm, treated with a radical hysterectomy and pelvic lymphadenectomy between 1985 and 2020 were selected from the databases of the Amsterdam University Medical Center and the University Medical Center Groningen. The specimens of patients with LNM were revised by expert pathologists. The incidence of LNM was calculated. The associations between LNM and DOI, diameter, histological type, clinical visibility and lymphovascular space invasion (LVSI) were evaluated by calculating odds ratios using logistic regression. Results: Of the 389 patients included, 10 had pathologically confirmed LNM (2.6%, 95% confidence interval=1.3%-4.5%). In case of LVSI, univariate analysis showed an increased risk of LNM (p=0.003 and p=0.012, respectively). No difference in LNM was found between lesions diagnosed by microscopy and clinically visible lesions. No LNM were found in patients without LVSI and a DOI of ≤3 mm. Conclusion: For patients with stage IA cervical cancer with a diameter >7 mm, we recommend considering a pelvic lymph node assessment in case of DOI >3 mm and/or presence of LVSI. [ABSTRACT FROM AUTHOR]

Background: Lymph node metastasis is an important prognostic factor in locally advanced cervical cancer (LACC). No imaging method can successfully detect all (micro)metastases. This may result in (lymph node) recurrence after chemoradiation. We hypothesized that lymphatic mapping could identify nodes at risk and if radiation treatment volumes are adapted based on the lymphatic map, (micro)metastases not shown on imaging could be treated. We investigated the feasibility of lymphatic mapping to image lymph nodes at risk for (micro)metastases in LACC and assessed the radiotherapy dose on the nodes at risk. Methods: Patients with LACC were included between July 2020 and July 2022. Inclusion criteria were: ≥ 18 years old, intended curative chemoradiotherapy, investigation under anesthesia. Exclusion criteria were: pregnancy and extreme obesity. All patients underwent abdominal MRI, [18F]FDG-PET/CT and lymphatic mapping after administration of 6–8 depots of 99mTc]Tc-nanocolloid followed by planar and SPECT/CT images 2–4 and 24 h post-injection. Results: Seventeen patients participated. In total, 40 nodes at risk were visualized on the lymphatic map in 13/17 patients with a median of two [range 0–7, IQR 0.5–3] nodes per patient, with unilateral drainage in 4/13 and bilateral drainage in 9/13 patients. No complications occurred. The lymphatic map showed more nodes compared to suspicious nodes on MRI or [18F]FDG-PET/CT in 8/14 patients. Sixteen patients were treated with radiotherapy with 34 visualized nodes on the lymphatic map. Of these nodes, 20/34 (58.8%) received suboptimal radiotherapy: 7/34 nodes did not receive radiotherapy at all, and 13/34 received external beam radiotherapy (EBRT), but no simultaneous integrated boost (SIB). Conclusion: Lymphatic mapping is feasible in LACC. Almost 60% of nodes at risk received suboptimal treatment during chemoradiation. As treatment failure could be caused by (micro)metastasis in some of these nodes, including nodes at risk in the radiotherapy treatment volume could improve radiotherapy treatment outcome in LACC. Trail registration The study was first registered at the International Clinical Trial Registry Platform (ICTRP) under number of NL9323 on 4 March 2021. Considering the source platform was not operational anymore, the study was retrospectively registered again on February 27, 2023 at CilicalTrials.gov under number of NCT05746156. [ABSTRACT FROM AUTHOR]

Today, the patient who is diagnosed with early cervical cancer is offered a variety of treatments apart from standard therapy. Patients can be treated with a less radical hysterectomy (RH) regarding parametrectomy, a trachelectomy either vaginal or abdominal, and this can be performed through a minimal invasive or open procedure. All this in combination with nerve sparing and/or sentinel node technique. Level 1 evidence for the oncological safety of all these modifications is only available from 3 randomized controlled trials (RCTs). Two RCTs on more or less radical parametrectomy both showed that oncological safety was not compromised by doing less radical surgery. Because of the heterogeneity of the patient population and the high frequency of adjuvant radiotherapy, the true impact of surgical radicality cannot be assessed. Regarding the issue of oncological safety of fertility sparing treatments, case-control and retrospective case series suggest that trachelectomy is safe as long as the tumor diameter does not exceed 2 cm. Recently, both a RCT and 2 case-control studies showed a survival benefit for open surgery compared to minimally invasive surgery, whereas many previous case-control and retrospective case series on this subject did not show impaired oncological safety. In a case-control study the survival benefit for open surgery was restricted to the group of patients with a tumor diameter more than 2 cm. Although modifications of the traditional open RH seem safe for tumors with a diameter less than 2 cm, ongoing prospective RCTs and observational studies should give the final answer. [ABSTRACT FROM AUTHOR]

The indoleamine 2,3-dioxygenase (IDO) enzyme can act as an immunoregulator by inhibiting T cell function via the degradation of the essential amino acid tryptophan (trp) into kynurenine (kyn) and its derivates. The kyn/trp ratio in serum is a prognostic factor for cervical cancer patients; however, information about the relationship between serum levels and IDO expression in the tumor is lacking. IDO expression was studied in 71 primary and 14 paired metastatic cervical cancer samples by various immunohistochemical (IHC) techniques, including 7-color fluorescent multiparameter IHC, and the link between the concentration of IDO metabolites in serum, clinicopathological characteristics, and the presence of (proliferating) T cells (CD8, Ki67, and FoxP3) was examined. In addition, we compared the relationships between IDO1 and IFNG gene expression and clinical parameters using RNAseq data from 144 cervical tumor samples published by The Cancer Genome Atlas (TCGA). Here, we demonstrate that patchy tumor IDO expression is associated with an increased systemic kyn/trp ratio in cervical cancer (P = 0.009), whereas marginal tumor expression at the interface with the stroma is linked to improved disease-free (DFS) (P = 0.017) and disease-specific survival (P = 0.043). The latter may be related to T cell infiltration and localized IFNγ release inducing IDO expression. Indeed, TCGA analysis of 144 cervical tumor samples revealed a strong and positive correlation between IDO1 and IFNG mRNA expression levels (P < 0.001) and a significant association with improved DFS for high IDO1 and IFNG transcript levels (P = 0.031). Unexpectedly, IDO+ tumors had higher CD8+Ki67+ T cell rates (P = 0.004). Our data thus indicate that the serum kyn/trp ratio and IDO expression in primary tumor samples are not clear-cut biomarkers for prognosis and stratification of patients with early stage cervical cancer for clinical trials implementing IDO inhibitors. Rather, a marginal IDO expression pattern in the tumor dominantly predicts favorable outcome, which might be related to IFNγ release in the cervical tumor microenvironment. [ABSTRACT FROM AUTHOR]

Human papillomavirus (HPV) infection drives tumorigenesis in almost all cervical cancers and a fraction of vulvar and penile cancers. Due to increasing incidence and low vaccination rates, many will still have to face HPV-related morbidity and mortality in the upcoming years. Current treatment options (i.e., surgery and/or chemoradiation) for urogenital (pre-)malignancies can have profound psychosocial and psychosexual effects on patients. Moreover, in the setting of advanced disease, responses to current therapies remain poor and nondurable, highlighting the unmet need for novel therapies that prevent recurrent disease and improve clinical outcome. Immunotherapy can be a useful addition to the current therapeutic strategies in various settings of disease, offering relatively fewer adverse effects and potential improvement in survival. This review discusses immune evasion mechanisms accompanying HPV infection and HPV-related tumorigenesis and summarizes current immunotherapeutic approaches for the treatment of HPV-related (pre-)malignant lesions of the uterine cervix, vulva, and penis. [ABSTRACT FROM AUTHOR]

Upon discovery of lymph node metastasis during radical hysterectomy with pelvic lymphadenectomy in early-stage cervical cancer, the gynaecologist may pursue one of two treatment strategies: abandonment of surgery followed by primary (chemo)radiotherapy (PRT) or completion of radical hysterectomy, followed by adjuvant (chemo)radiotherapy (RHRT). Current guidelines recommend PRT over RHRT, as combined treatment is presumably associated with increased morbidity. However, this review of literature suggests there are no significant differences in survival and recurrence and total proportions of adverse events between treatment strategies. Additionally, both strategies are associated with varying types of adverse events, and affect quality of life and sexual functioning differently, both in the short and long term. Although total proportions of adverse events were comparable between treatment strategies, lower extremity lymphoedema was reported more often after RHRT and symptom experience (e.g. distress from bladder or bowel problems) and sexual dysfunction more often after PRT. As reporting of adverse events, quality of life and sexual functioning were not standardised across the articles included, and covariate adjustment was not conducted in most of the analyses, comparability of studies is hampered. Accumulating retrospective evidence suggests no major differences on oncological outcome and morbidity after PRT and RHRT for intraoperatively discovered lymph node metastasis in cervical cancer. However, conclusions should be considered cautiously, as all studies were of retrospective design with small sample sizes. Still, treatment strategies seem to affect adverse events, quality of life and sexual functioning in different ways, allowing room for shared decision-making and personalised treatment. [ABSTRACT FROM AUTHOR]

Imaging is essential in detecting lymph node metastases for radiotherapy treatment planning in locally advanced cervical cancer (LACC). There are not many data on the performance of 18F]FDG-PET(CT) in showing lymph node metastases in LACC. We pooled sensitivity and specificity of 18F]FDG-PET(CT) for detecting pelvic and/or para-aortic lymph node metastases in patients with LACC. Also, the positive and negative posttest probabilities at high and low levels of prevalence were determined. MEDLINE and EMBASE searches were performed and quality characteristics assessed. Logit-sensitivity and logit-specificity estimates with corresponding standard errors were calculated. Summary estimates of sensitivity and specificity with corresponding 95% confidence intervals (CIs) were calculated by anti-logit transformation. Positive and negative likelihood ratios (LRs) were calculated from the mean logit-sensitivity and mean logit-specificity and the corresponding standard errors. The posttest probabilities were determined by Bayesian approach. Twelve studies were included with a total of 778 patients aged 10–85 years. For pelvic nodes, summary estimates of sensitivity, specificity, LR+ and LR- were: 0.88 (95%CI: 0.40–0.99), 0.93 (95%CI: 0.85–0.97), 11.90 (95%CI: 5.32–26.62) and 0.13 (95%CI: 0.01–1.08). At the lowest prevalence of 0.15 the positive predictive value (PPV) and negative predictive value (NPV) were 0.68 and 0.98, at the highest prevalence of 0.65, 0.96 and 0.81. For the para-aortic nodes, the summary estimates of sensitivity, specificity LR+ and LR- were: 0.40 (95%CI: 0.18–0.66), 0.93 (95%CI: 0.91–0.95), 6.08 (95%CI: 2.90–12.78) and 0.64 (95%CI: 0.42–0.99), respectively. At the lowest prevalence of 0.17 the PPV and NPV were 0.55 and 0.88, at the highest prevalence of 0.50, 0.86 and 0.61. The PPV and NPV of 18F]FDG-PET(CT) showing lymph node metastases in patients with LACC improves with higher prevalence. Prevalence and predictive values should be taken into account when determining therapeutic strategies based on 18F]FDG-PET(CT). • Prevalence of a tumor positive node is 0.15–0.65 for pelvic and 0.15–0.70 for para-aortic nodes in 778 LACC patients. • Pelvic nodes: PPV and NPV for the lowest prevalence were 0.68 and 0.98 and for the highest prevalence 0.96 and 0.81. • Para-aortic nodes: PPV and NPV for the lowest prevalence were 0.55 and 0.88 and for the highest prevalence 0.86 and 0.61. • Prevalence and predictive values need to be considered when determining therapeutic strategies based on 18F]FDG-PET(CT). [ABSTRACT FROM AUTHOR]

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. 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. 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. 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. KWF Dutch Cancer Society. [ABSTRACT FROM AUTHOR]

Up to 26% of patients with early-stage cervical cancer experience relapse after primary surgery. However, little is known about which factors influence prognosis following disease recurrence. Therefore, our aims were to determine post-recurrence disease-specific survival (PR-DSS) and to identify respective prognostic factors for PR-DSS. Data from 528 patients with early-stage cervical cancer who relapsed after primary surgery performed between 2007 and 2016 were obtained from the SCANN study (Surveillance in Cervical CANcer). Factors related to the primary disease and recurrence were combined in a multivariable Cox proportional hazards model to predict PR-DSS. The 5-year PR-DSS was 39.1% (95% confidence interval [CI] 22.7%–44.5%), median disease-free interval between primary surgery and recurrence (DFI1) was 1.5 years, and median survival after recurrence was 2.5 years. Six significant variables were identified in the multivariable analysis and were used to construct the prognostic model. Two were related to primary treatment (largest tumour size and lymphovascular space invasion) and four to recurrence (DFI1, age at recurrence, presence of symptoms, and recurrence type). The C-statistic after 10-fold cross-validation of prognostic model reached 0.701 (95% CI 0.675–0.727). Three risk-groups with significantly differing prognoses were identified, with 5-year PR-DSS rates of 81.8%, 44.6%, and 12.7%. We developed the robust model of PR-DSS to stratify patients with relapsed cervical cancer according to risk profiles using six routinely recorded prognostic markers. The model can be utilised in clinical practice to aid decision-making on the strategy of recurrence management, and to better inform the patients. • The 5-year post-recurrence disease-specific survival (PR-DSS) rate was 39.1% in patients with early-stage cervical cancer. • The strongest factors for PR-DSS were primary tumour size and the presence of symptoms at diagnosis of recurrence. • The presence of symptoms at recurrence remained a significant prognostic factor after correction for lead-time bias. • PR-DSS was best in patients without LN involvement or LVSI suffering from solitary asymptomatic recurrence. [ABSTRACT FROM AUTHOR]

Current guidelines for surveillance strategy in cervical cancer are rigid, recommending the same strategy for all survivors. The aim of this study was to develop a robust model allowing for individualised surveillance based on a patient's risk profile. Data of 4343 early-stage patients with cervical cancer treated between 2007 and 2016 were obtained from the international SCCAN (Surveillance in Cervical Cancer) consortium. The Cox proportional hazards model predicting disease-free survival (DFS) was developed and internally validated. The risk score, derived from regression coefficients of the model, stratified the cohort into significantly distinctive risk groups. On its basis, the annual recurrence risk model (ARRM) was calculated. Five variables were included in the prognostic model: maximal pathologic tumour diameter; tumour histotype; grade; number of positive pelvic lymph nodes; and lymphovascular space invasion. Five risk groups significantly differing in prognosis were identified with a five-year DFS of 97.5%, 94.7%, 85.2% and 63.3% in increasing risk groups, whereas a two-year DFS in the highest risk group equalled 15.4%. Based on the ARRM, the annual recurrence risk in the lowest risk group was below 1% since the beginning of follow-up and declined below 1% at years three, four and >5 in the medium-risk groups. In the whole cohort, 26% of recurrences appeared at the first year of the follow-up, 48% by year two and 78% by year five. The ARRM represents a potent tool for tailoring the surveillance strategy in early-stage patients with cervical cancer based on the patient's risk status and respective annual recurrence risk. It can easily be used in routine clinical settings internationally. • The recurrence risk model in cervical cancer was composed of five prognostic factors. • The developed annual recurrence risk model (ARRM) stratifies the cohort into five significantly distinctive risk groups. • The ARRM represents a powerful tool for tailoring of appropriate surveillance strategy. • The ARRM can easily be used in routine clinical settings internationally. [ABSTRACT FROM AUTHOR]

Purpose: Preclinical data indicate a synergistic effect on apoptosis between irradiation and recombinant human (rh) tumor necrosis factor–related apoptosis inducing ligand (TRAIL), making the TRAIL death receptors (DR) interesting drug targets. The aim of our study was to analyze the expression of DR4, DR5, and TRAIL in cervical cancer and to determine their predictive and prognostic value. Methods and Materials: Tissue microarrays were constructed from tumors of 645 cervical cancer patients treated with surgery and/or (chemo-)radiation between 1980 and 2004. DR4, DR5, and TRAIL expression in the tumor was studied by immunohistochemistry and correlated to clinicopathological variables, response to radiotherapy, and disease-specific survival. Results: Cytoplasmatic DR4, DR5, and TRAIL immunostaining were observed in cervical tumors from 99%, 88%, and 81% of the patients, respectively. In patients treated primarily with radiotherapy, TRAIL-positive tumors less frequently obtained a pathological complete response than TRAIL-negative tumors (66.3% vs. 79.0 %; in multivariate analysis: odds ratio: 2.09, p ≤0.05). DR4, DR5, and TRAIL expression were not prognostic for disease-specific survival. Conclusions: Immunostaining for DR4, DR5, and TRAIL is frequently observed in the cytoplasm of tumor cells in cervical cancer patients. Absence of TRAIL expression was associated with a higher pathological complete response rate to radiotherapy. DR4, DR5, or TRAIL were not prognostic for disease-specific survival. [Copyright &y& Elsevier]