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BackgroundRadical hysterectomy with pelvic lymphadenectomy represents the standard treatment for early-stage cervical cancer. Results from a recent randomized controlled trial demonstrate that minimally invasive surgery is inferior to laparotomy with regards to disease-free and overall survival.Primary ObjectiveTo investigate the oncologic safety of robot-assisted surgery for early-stage cervical cancer as compared with standard laparotomy.Study HypothesisRobot-assisted laparoscopic radical hysterectomy is non-inferior to laparotomy in regards to recurrence-free survival with the advantage of fewer post-operative complications and superior patient-reported outcomes.Trial DesignProspective, multi-institutional, international, open-label randomized clinical trial. Consecutive women with early-stage cervical cancer will be assessed for eligibility and subsequently randomized 1:1 to either robot-assisted laparoscopic surgery or laparotomy. Institutional review board approval will be required from all participating institutions. The trial is coordinated from Karolinska University Hospital, Sweden.Major Inclusion/Exclusion CriteriaWomen over 18 with cervical cancer FIGO (2018) stages IB1, IB2, and IIA1 squamous, adenocarcinoma, or adenosquamous will be included. Women are not eligible if they have evidence of metastatic disease, serious co-morbidity, or a secondary invasive neoplasm in the past 5 years.Primary EndpointRecurrence-free survival at 5 years between women who underwent robot-assisted laparoscopic surgery versus laparotomy for early-stage cervical cancer.Sample SizeThe clinical non-inferiority margin in this study is defined as a 5-year recurrence-free survival not worsened by >7.5%. With an expected recurrence-free survival of 85%, the study needs to observe 127 events with a one-sided level of significance (α) of 5% and a power (1−β) of 80%. With 5 years of recruitment and 3 years of follow-up, the necessary number of events will be reached if the study can recruit a total of 768 patients.Estimated Dates for Completing Accrual and Presenting ResultsTrial launch is estimated to be May 2019 and the trial is estimated to close in May 2027 with presentation of data shortly thereafter.Trial RegistrationThe trial is registered at ClinicalTrials.gov (NCT03719547).

Objective To study the risk of adverse pregnancy outcomes in women with polycystic ovary syndrome, taking into account maternal characteristics and assisted reproductive technology.Design Population based cohort study.Setting Singleton births registered in the Swedish medical birth register between 1995 and 2007.Participants By linkage with the Swedish patient register, 3787 births among women with a diagnosis of polycystic ovary syndrome and 1 191 336 births among women without such a diagnosis.Main outcome measures Risk of adverse pregnancy outcomes (gestational diabetes, pre-eclampsia, preterm birth, stillbirth, neonatal death, low Apgar score (<7 at five minutes), meconium aspiration, large for gestational age, macrosomia, small for gestational age), adjusted for maternal characteristics (body mass index, age), socioeconomic factors (educational level, and cohabitating with infant’s father), and assisted reproductive technology.Results Women with polycystic ovary syndrome were more often obese and more commonly used assisted reproductive technology than women without such a diagnosis (60.6% v 34.8% and 13.7% v 1.5%). Polycystic ovary syndrome was strongly associated with pre-eclampsia (adjusted odds ratio 1.45, 95% confidence interval 1.24 to 1.69) and very preterm birth (2.21, 1.69 to 2.90) and the risk of gestational diabetes was more than doubled (2.32, 1.88 to 2.88). Infants born to mothers with polycystic ovary syndrome were more prone to be large for gestational age (1.39, 1.19 to 1.62) and were at increased risk of meconium aspiration (2.02, 1.13 to 3.61) and having a low Apgar score (<7) at five minutes (1.41, 1.09 to 1.83).Conclusions Women with polycystic ovary syndrome are at increased risk of adverse pregnancy and birth outcomes that cannot be explained by assisted reproductive technology. These women may need increased surveillance during pregnancy and parturition.

Introduction/Background*Identifying risk factors for lymph node metastases in early-stage cervical cancer may aid in tailoring treatment. Unfortunately, early-stage cervical cancer research is often hampered by small sample sizes.A natural solution to increase sample size is to incorporate data from multiple sources, traditionally done through centralization. Unfortunately, this approach presents disadvantages concerning privacy protection. Alternatively, models can be trained in one source and tested in another setting, sharing only the model coefficients (figure 1). This approach does not disclose any privacy-sensitive information. Additionally, external validation provides stronger evidence on the generalizability of the obtained statistical model.In this study, we used the alternative approach to increase sample size and identify risk factors for postoperative lymph node metastases (pN1) in early-stage cervical cancer.MethodologyWe conducted an international observational cohort study using data from the Danish Gynaecologic Cancer Database (DGCD) and the Netherlands Cancer Registry (NCR). We included women diagnosed with early-stage cervical squamous cell carcinoma, adenocarcinoma or adenosquamous carcinoma between 2005–2017, who were treated with radical surgery.We generated two logistic regression models to identify risk factors for pN1. Model A was trained on NCR data and tested with DGCD data, while model B was obtained the other way around. The performance of each model was assessed using areas under the curve (AUCs).Result(s)*A total of 2735 patients were included in the analyses.In model A – trained on data from 1476 Dutch patients and tested with data from 1259 Danish patients – tumour size (odds ratio 1.62; 95% confidence interval [1.37–1.91]), depth of invasion (1.30 [1.12–1.53]) and LVSI (5.13 [3.50–7.52]) were identified as risk factors for pN1, and body mass index as protective factor (0.80 [0.67–0.95].In model B, trained on Danish data (n=1259) and tested with Dutch data (n=1476), tumour size (1.48 [1.23–1.79]), depth of invasion (1.27 [1.04–1.54]) and LVSI (3.85 [2.53–5.86]) were associated with increased risk of pN1.External validation of model A and B both showed AUCs of 0.78 (figure 2).Abstract 1180 Figure 1A privacy-preserving alternative to small sample analysis. Model A is trained on data from the NCR and tested on DGCD data. Model B was obtained the other way around. Only model coefficients need to be shared and, thereby, no privacy-sensitive information is disclosedAbstract 1180 Figure 2Areas under the curve for two models identififying risk factors for postoperative lymph node metastases in earl-stage cervical cancer. 2A: Model A trained with NCR data, tested on DGCD data; 2B: Model B trained with DGCD data, tested on NCR data.Conclusion*Tumour size, depth of invasion and LVSI were identified as risk factors for pN1 in both models.Separate models, containing either Danish or Dutch data have shown to be valid by privacy-preserving external validation.

ObjectiveA high quality end-expiratory breath sample is required for a reliable gastrointestinal breath test result. Oxygen (O2) concentration in the breath sample can be used as a quality marker. This study investigated the characteristics of O2 concentration in the breath sample and the impact of using a correction factor in real-time breath measurement.DesignThis study includes two separate groups of patient data. Part 1 of the study analysed the patient’s ability to deliver end-expiratory breath samples over a 2-year period (n=564). Part 2 of the study analysed a separate group of patients (n=47) with additional data to investigate the O2 characteristics and the role of correction factor in breath test.ResultsThe results indicated 95.4% of 564 patients were able to achieve an O2 concentration below 14% in their end-expiratory breath. Part 2 of the study revealed that the distribution of O2 concentration was between 9.5% and 16.2%. Applying a correction factor to predict the end-expiratory H2 and CH4 values led to an average measurement error of −36.4% and −12.8%, respectively.ConclusionThe majority of patients are able to deliver a high quality end-expiratory breath sample, regardless of age or gender. The correction factor algorithm is unreliable when predicting the end-expiratory result at 15% O2 and it would have resulted in false negative result for 50% of the positive cases in this study. It has also indicated that the continuous O2 measurement is essential to ensure breath sample quality by preventing secondary breathing during real-time breath collection.

Introduction/BackgroundRadical cytoreductive surgery is the most important prognostic factor for survival in women with advanced epithelial ovarian cancer (EOC). Extra-pelvic procedures, including bowel resections, are often necessary to achieve complete tumor resection. Anastomotic leakage (AL) is a severe postoperative complication with risk of perioperative death and delay in time to start of adjuvant chemotherapy. The objective of this study was to evaluate AL rates in relation to surgical specialty and complexity score.MethodologyConsecutive women with advanced EOC who underwent bowel resection as part of cytoreductive surgery at Karolinska University Hospital between 2004–2011 and 2014–2016 were identified in hospital data bases. Descriptive statistics was performed.ResultsNinety-three and 101 women were analyzed in the early (2004–2011) and late (2014–2016) cohorts respectively. Demographic data was similar between groups. Bowel surgery performed by colorectal surgeons decreased from 89% to 20% (p<0.001). The rate of upfront surgery increased from 70% to 99% (p<0.001) and surgical complexity score (SCS) from 6.3 to 9.8 (p<0.001) between the cohorts. AL decreased from 6.5% to 4% (p=0.52).ConclusionDespite a significant increase of bowel resections performed by gynecologic oncologists, upfront surgery and SCS, there was no increase in AL rate. Bowel surgery can safely be performed by trained gynecological oncologists.DisclosureNothing to disclose.

Introduction/Background*The impact of lymph node (LN) micrometastases (MIC) in cervical cancer patients remains a controversial topic given their low incidence and good prognosis of patients managed by primary surgery.We aim to evaluate the prognostic significance of MIC and isolated tumour cells (ITC) in a large cohort of patients from the SCCAN retrospetive study (Surveillance in Cervical CANcer). SCCAN study analysed data from more than 4300 patients with early stage cervical cancer treated by primary surgery at 20 large tertiary institutions from Europe, North America, South America and Australia.MethodologyIn this SCCAN sub-study, we included patients with early stage cervical cancer (T1a1 LVSI+ – T2b) treated between 2007 and 2016 with at least 1-year follow-up data availability, who underwent primary surgery including sentinel lymph node (SLN) biopsy and in whom SLNs were processed by pathological ultrastaging protocol.Result(s)*Out of 969 included patients with at least 1 SLN detected, 174 (18%) had positive LN (table 1). Maximal tumour diameter >2cm, positive LVSI, grade ≥ 2, uncommon histological type (neuroendocrine, sarcoma, etc.) and macrometstasis (MAC) or MIC in LN were factors associated with significantly decreased five-years disease free survival (DFS) (table 2). MAC, MIC or ITC was the largest LN metastasis in 84 (9%), 59 (6%) and 31 (3%) cases respectively. Adjuvant (chemo)radiation was administred in 89%, 85% and 58% of patients with MAC, MIC and ITC. DFS reached 75%, 73% and 83% in patients with MAC, MIC and ITC compared with 90% in the N0 patients. Patients with MAC and MIC had significantly decreased DFS than those with N0 disease (HR=2.36 and 2.55).Abstract 898 Figure 1Abstract 898 Table 1Data summary (N = 969) Characteristics Description Tracer type Radiocolloid 423 (43.7%) Dye 662 (68.3%) ICG 220 (22.7%) No. of SLN detected Mean ± SD 3.2 ± 2.2 Largest type of metastasis in LN including SLN Negative 795 (82.0%) ITC 31 (3.2%) MIC 59 (6.1%) MAC 84 (8.7%) Surgical approach Open 575 (59.3%) Robotic 195 (20.1%) Laparoscopic 199 (21.5%) Tumour histotype Squamous 605 (62.4%) Adenocarcinoma 287 (29.6%) Adenosquamous 50 (5.2%) Neuroendocrine 18 (1.9%) Other 9 (0.9%) Grade 1 149 (15.4%) 2 406 (41.9%) 3 246 (25.4%) N/A 168 (17.3%) LVSI No 316 (32.6%) Yes 351 (36.2%) N/A 302 (31.2%) Maximal pathologic tumour diameter [mm] Mean ± SD 20.6 ± 13.7 Median (IQR) 19 (10; 30) < 0.5 cm 73 (7.5%) 0.5–1.99 cm 424 (43.8%) 2–3.99 cm 376 (38.8%) ≥ 4 cm 96 (9.9%) Adjuvant therapy 312 (32.2%) if yes: radiotherapy 153 (49.0%) chemoradiotherapy 136 (43.6%) chemotherapy 18 (5.8%) chemoradiotherapy + chemotherapy 5 (1.6%) Recurrence 117 (12.1%) Abstract 898 Table 2Univariate analysis of factors associated with disease-free survival (N = 969) Predictor Category n HR (95% CI ) p-value Surgical approach Open 575 Ref. Robotic 195 1.21 (0.74; 1.97) 0.439 Laparoscopic 141 1.51 (0.93; 2.45) 0.097 Combined 58 1.06 (0.48; 2.31) 0.888 Tumour diameter < 0.5 cm 73 Ref. 0.5–1.99 cm 424 1.67 (0.51; 5.47) 0.399 2–3.99 cm 376 3.98 (1.25 ; 12.69) 0.019 ≥ 4 cm 96 6.35 (1.91 ; 21.13) 0.003 LVSI No 316 Ref. Yes 351 2.31 (1.47 ; 3.63) < 0.001 Tumour histotype Squamous 605 Ref. Adenocarc. 287 1.13 (0.75; 1.71) 0.554 Adenosquamous 50 1.38 (0.66; 2.89) 0.385 Other 27 3.03 (1.45 ; 6.31) 0.003 Grade 1 149 Ref. 2 406 2.08 (1.02 ; 4.22) 0.044 3 246 3.35 (1.64 ; 6.85) < 0.001 Largest type of metastasis in LN Negative 795 Ref. ITC 31 1.67 (0.68; 4.14) 0.264 MIC 59 2.55 (1.47 ; 4.43) < 0.001 MAC 84 2.36 (1.44 ; 3.87) < 0.001 Largest type of metastasis in LN Negative 795 Ref. ITC 31 1.67 (0.68; 4.14) 0.264 MIC+MAC 143 2.44 (1.63 ; 3.64) < 0.001 Conclusion*Early-stage cervical cancer patients with MIC in pelvic LN have significantly decreased DFS. Their management should follow the same principles as in patients with MAC.

Introduction/Background*Up to 26% of early-stage cervical cancer patients relapse after primary surgical treatment. However, little is known about the factors affecting prognosis following disease recurrence. Hence, the aim of this study was to evaluate post-recurrence disease-specific survival (PR-DSS) and to identify respective prognostic factors.MethodologyData from 528 early-stage cervical cancer patients who relapsed after primary surgical treatment performed between 2007 and 2016 were obtained from the SCCAN study (Surveillance in Cervical CANcer). Parameters related both to primary disease and recurrence diagnosis were combined to develop a multivariable Cox proportional hazards model predicting PR-DSS.Result(s)*Five-year PR-DSS reached 39.1% (95% confidence interval: 22.7% – 44.5%) with median disease-free survival between primary surgery and recurrence diagnosis (DFI1) of 1.5 years and median survival after recurrence of 2.5 years. Six variables significant in multivariable analysis were included in the PR-DSS prognostic model; two related to the primary disease characteristics: maximal diameter of the tumour and lymphovascular space invasion; and four related to the recurrence diagnosis: DFI1, age, presence of symptoms, and recurrence localization (table 1). C-statistics of the final model after 10-fold internal validation equalled 0.701 (95% CI: 0.675 – 0.727). Five risk groups significantly differing in prognosis were identified, with 5-year DSS after recurrence of 85.6%, 62.0%, 46.7, 19.7%, and 0% in the highest risk group (figure 1).Abstract 942 Table 1Multivariable Cox regression model for prediction of disease-specific death after recurrence Predictor B SE(β) HR 95% CI P-value Points (max. 100) Years from surgery to recurrence > 1 year Reference 0 < 1 year 0.516 0.132 1.676 1.294–2.169 < 0.001 11 Age at recurrence < 65 years Reference 0 65+ years 0.543 0.187 1.720 1.192–2.482 0.004 12 Maximal pathologic tumour diameter* < 0.5 cm Reference 0 0.5–1.9 cm 0.947 0.602 2.577 0.792–8.380 0.116 20 2.0–3.9 cm 1.269 0.593 3.557 1.113–11.374 0.032 27 ≥ 4.0 cm 1.481 0.598 4.397 1.363–14.184 0.013 31 LVSI* No/unknown Reference 0 Yes 0.672 0.148 1.957 1.463–2.619 < 0.001 14 Recurrence symptoms No Reference 0 Yes/unknown 0.788 0.151 2.199 1.634–2.958 < 0.001 17 Recurrence localization Isolated Reference 0 Multiple 0.687 0.135 1.987 1.526–2.587 < 0.001 15 *Characteristics at the time of primary surgeryAbstract 942 Figure 1Disease specific survival of all patients stratified by risk score (N=528). Time zero was set at date of recurrence diagnosisConclusion*We have developed the first robust model of disease-specific survival after recurrence stratifying relapsing cervical cancer patients according to their risk profile using six traditional prognostic markers. The strongest factor related to the length of post-recurrence survival was the largest size of the primary tumour, followed by the presence of symptoms at the time of diagnosis, which remained significant even after correction for lead-time bias.

Introduction/Background*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 and comprehensive model allowing for individualised surveillance strategy based on risk profile of early-stage cervical cancer patients that were referred for surgical treatment with curative intent.MethodologyThe data of 4,343 cervical cancer patients with pathologically confirmed early-stage cervical cancer treated between 2007 and 2016 were obtained from SCANN consortium centres of excellence (Surveillance in Cervical CANcer). Only patients with complete key predictor variables and a minimum of one-year follow-up data availability were included. Based on the prognostic markers, a multivariable Cox proportional hazards model predicting disease-free survival (DFS) was developed and internally validated. A 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 by conditional survival analysis.Result(s)*Five variables significant in multivariable analysis of recurrence risk were included in the prognostic model: maximal pathologic tumour diameter, tumour histotype, tumour grade, the number of positive pelvic lymph nodes, and lymphovascular space invasion (table 1). The model was ten-fold internally cross-validated with the average AUC of 0.732. Five risk groups significantly differing in prognosis were identified: with five-year DFS of 97.5%, 94.7%, 85.2%, and 63.3% in consecutive increasing risk groups, while two-year DFS in the highest risk group equalled 15.4%. Based on ARRM, the annual recurrence risk in the lowest risk group was below 1% in the first year of follow-up and declined below 1% at years three, four, and >5 in the three medium-risk groups (figure 1). The proportion of pelvic recurrences declined in groups with the growing risk. 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.Abstract 960 Table 1Multivariate model for risk of recurrence predictionAbstract 960 Figure 1ARRM: Landmark analysis of the annual probability of recurrence after surgery. N/A not analysed.Conclusion*ARRM represents a powerful tool for tailoring the surveillance strategy in early-stage cervical cancer patients based on the patient´s risk status and respective annual recurrence risk. It can easily be utilised in routine clinical settings internationally.

ObjectivesTo compare disease-free survival (DFS) between patients who underwent open (ORT) versus minimally invasive (MIS) radical trachelectomy (RT) [laparoscopic (LRT) or robotic (RRT)].MethodsEligibility criteria included1) RT and pelvic lymphadenectomy with/without sentinel lymph node mapping, 2) 1/2005 to 12/2017 3) squamous, adenocarcinoma, or adenosquamous histology, 4) stage IA2-IB1, 5) tumors ≤2 cm, 6) 15 or more cases per center.ResultsA total of 698 patients [open (n=388) vs. MIS (310)] were included. The median follow-up time was 40.9 months (range, 1–179.1) [MIS 38.6 (range, <1–128.1) vs. open 68.3 (range, <1–200.8) (p<0.001)]. MIS patients had smaller tumors (no visible lesion: 76.8% vs 57.0%, < 1 cm: 1.9% vs. 2.8%, 1–2 cm: 21.3% vs. 40.2%, p<0.001) and lower rates of residual disease (42.9% vs. 56.2% p<0.001). (table 1) There were no differences in rates of parametrial involvement (2.1% vs. 1.3% p=0.055), vaginal involvement (0.8% vs. 1.4% p=0.198), positive margins (2.9% vs. 3.5% p=0.766), or positive nodes (7.2% vs. 4.5%, p=4.02). (table 2) Patients who underwent open RT had longer hospital stay (6 (1–23) vs 2 (0–24) days, p<0.001) and received more adjuvant therapy (12.7% vs. 5.9%, p=0.003). MIS patients had more readmissions (11.0% vs. 1.8%, p<0.001) and reoperations (4.8% vs. 1.5%, p=0.01). There was no difference in recurrence rate (6.4% vs. 5.7%, p=0.7492), DFS (p=0.46) or OS (p=0.91) between MIS and open surgical approaches (figure 1).Abstract 22 Table 1Patient characteristicsAbstract 22 Table 2Tumor pathology and adjuvant treatmentAbstract 22 Figure 1Kaplan-Meier plot of disease-free survival with number at riskAbstract 22 Figure 2Kaplan-Meier curve of overall survivalConclusionsSurgical approach in radical trachelectomy for low-risk cervical cancer was not associated with differences in recurrence rates or survival. MIS had worse perioperative outcomes.

To the Editor: Currently, the threshold for radical hysterectomy is between stages T1a2 and T1b1 — that is, a depth of invasion of less than 5 mm. 1 Typically, patients at these stages undergo conization for tumor-size confirmation before hysterectomy. The criteria in the SHAPE (Simple Hysterectomy and Pelvic Node Assessment) trial by Plante et al. (Feb. 29 issue) 2 push the threshold for simple hysterectomy to 2 cm of tumor size in combination with limited stromal invasion. In that case, conization may fail to result in free margins. In the SHAPE trial, 9% of the patients undergoing simple hysterectomy received adjuvant . . .