Introducing a novice surgeon to an experienced robotic gynaecological oncology team: An observational cohort study on the impact of a structured curriculum on outcomes of cervical cancer surgery

Objective: To evaluate the effect on patient outcomes when introducing a novice robotic surgeon, trained in accordance with a structured learning curriculum, to an experienced robotic surgery team treating cervical cancer patients. Methods: Patients with early-stage cervical cancer who were treated with primary robot-assisted surgery between 2007 and 2019 were retrospectively included. In addition to the 165 patients included in a former analysis, we included a further 61 consecutively treated patients and divided all 226 patients over three groups: early learning phase of 61 procedures without structured training (group 1), experienced phase of 104 procedures (group 2), and the 61 procedures during introduction of a novice with structured training (group 3). Risk-adjusted cumulative sum (RA-CUSUM) analysis was performed to assess the learning curve effect. Patient outcomes between the groups were compared. Results: Based on RA-CUSUM analysis, no learning curve effect was observed for group 3. Regarding surgical outcomes, mean operation time in group 3 was significantly shorter than group 1 (p < 0.001) and similar to group 2 (p = 0.96). Proportions of intraoperative and postoperative adverse events in group 3 were not significantly different from the experienced group (group 2). Regarding oncological outcomes, the 5-year disease-free survival, disease-specific survival, and overall survival in group 3 were not significantly different from the experienced group. Conclusions: Introducing a novice robotic surgeon, who was trained in accordance with a structured learning curriculum, resulted in similar patient outcomes as by experienced surgeons suggesting novices can progress through a learning phase without compromising outcomes of cervical cancer patients

Multi-modal volumetric concept activation to explain detection and classification of metastatic prostate cancer on PSMA-PET/CT

Explainable artificial intelligence (XAI) is increasingly used to analyze the behavior of neural networks. Concept activation uses human-interpretable concepts to explain neural network behavior. This study aimed at assessing the feasibility of regression concept activation to explain detection and classification of multi-modal volumetric data. Proof-of-concept was demonstrated in metastatic prostate cancer patients imaged with positron emission tomography/computed tomography (PET/CT). Multi-modal volumetric concept activation was used to provide global and local explanations. Sensitivity was 80% at 1.78 false positive per patient. Global explanations showed that detection focused on CT for anatomical location and on PET for its confidence in the detection. Local explanations showed promise to aid in distinguishing true positives from false positives. Hence, this study demonstrated feasibility to explain detection and classification of multi-modal volumetric data using regression concept activation.Comment: Accepted as: Kraaijveld, R.C.J., Philippens, M.E.P., Eppinga, W.S.C., J\"urgenliemk-Schulz, I.M., Gilhuijs, K.G.A., Kroon, P.S., van der Velden, B.H.M. "Multi-modal volumetric concept activation to explain detection and classification of metastatic prostate cancer on PSMA-PET/CT." MICCAI workshop on Interpretability of Machine Intelligence in Medical Image Computing (iMIMIC), 202

Symptomatic lymphocele after robot-assisted pelvic lymphadenectomy as part of the primary surgical treatment for cervical and endometrial cancer: a retrospective cohort study

Study Objectives: Pelvic lymph node dissection (PLND) is part of the primary treatment for early–stage cervical cancer and high–intermediate risk or high–risk endometrial cancer. Pelvic lymphocele is a postoperative complication of PLND, and when symptomatic, lymphoceles necessitate treatment. The aim of this study was to investigate the incidence and risk factors of symptomatic lymphocele after robot–assisted laparoscopic PLND in cervical and endometrial cancer. Design: Retrospective cohort study. Setting: Single–center academic hospital. Patients: Two hundred and fifty–eight patients with cervical cancer and 129 patients with endometrial cancer. Interventions: Pelvic lymphadenectomy by robot–assisted laparoscopic surgery. Measurements and Main Results: The authors retrospectively included all patients with early–stage cervical cancer and high–intermediate risk or high–risk endometrial cancer who underwent pelvic lymphadenectomy by robot–assisted laparoscopic surgery between 2008 and 2022. Medical records were reviewed for the occurrence of a symptomatic lymphocele. Univariate and multivariate logistic regression analyses were conducted to identify risk factors for developing a symptomatic lymphocele. In total, 387 patients, 258 with cervical cancer and 129 with endometrial cancer, were included in the study. The overall incidence of symptomatic lymphoceles was 9.6% with a median follow–up of 47 months [interquartile range 23–61]. For the entire cohort, smoking was the only significant risk factor for symptomatic lymphoceles identified in univariate (OR 2.47, 95% CI 1.19–5.11) and multivariate analysis (OR 2.42, 95% CI 1.16–5.07). For cervical cancer, body mass index (BMI) (OR 1.09, 95% CI 1.00–1.17) and prior abdominal surgery (OR 2.75, 95% CI 1.22–6.17) were also identified as significant independent risk factors. For endometrial cancer, age was identified as a significant independent risk factor (OR 0.90, 95% CI 0.83–0.97). Conclusion: This single–center cohort study demonstrated an incidence of almost 10% of symptomatic lymphoceles after robot–assisted laparoscopic PLND for cervical cancer and endometrial cancer, with a higher risk observed among patients who smoke at the time of diagnosis. Furthermore, risk factors differ between the 2 populations, necessitating further studies to establish risk models

Multi-center dosimetric predictions to improve plan quality for brachytherapy for cervical cancer treatment

BACKGROUND AND PURPOSE: Image-guided adaptive brachytherapy (IGABT) is an important modality in the cervical cancer treatment, and plan quality is sensitive to time pressure in the workflow. Patient anatomy-based quality-assurance (QA) with overlap volume histograms (OVHs) has been demonstrated to detect suboptimal plans (outliers). This analysis quantifies the possible improvement of plans detected as outliers, and investigates its suitability as a clinical QA tool in a multi-center setting. MATERIALS AND METHODS: In previous work OVH-based models were investigated for the use of QA. In this work a total of 160 plans of 68 patients treated in accordance with the current state-of-the-art IGABT protocol from Erasmus MC (EMC) were analyzed, with a model based on 120 plans (60 patients) from UMC Utrecht (UMCU). Machine-learning models were trained to define QA thresholds, and to predict dose D2cm3 to bladder, rectum, sigmoid and small bowel with the help of OVHs of the EMC cohort. Plans out of set thresholds (outliers) were investigated and retrospectively replanned based on predicted D2cm3 values. RESULTS: Analysis of replanned plans demonstrated a median improvement of 0.62 Gy for all Organs At Risk (OARs) combined and an improvement for 96 % of all replanned plans. Outlier status was resolved for 36 % of the replanned plans. The majority of the plans that could not be replanned were reported having implantation complications or insufficient coverage due to tumor geometry. CONCLUSION: OVH-based QA models can detect suboptimal plans, including both unproblematic BT applications and suboptimal planning circumstances in general. OVH-based QA models demonstrate potential for clinical use in terms of performance and user-friendliness, and could be used for knowledge transfer between institutes. Further research is necessary to differentiate between (sub)optimal planning circumstances

Progression-free survival in patients with Ga-68-PSMA-PET-directed SBRT for lymph node oligometastases

BACKGROUND: Prostate cancer oligometastatic disease can be treated using stereotactic body radiotherapy (SBRT) in order to postpone start of systemic treatments such as androgen deprivation therapy (ADT). 68Ga-PSMA-PET/CT imaging allows for diagnosis of oligometastases at lower PSA values. We analysed a cohort of patients with prostate cancer lymph node oligometastases detected on PSMA-PET/CT. MATERIALS AND METHODS: Ninety patients with metachronous oligometastatic prostate cancer received SBRT for 1-3 lymph node metastases diagnosed on 68Ga-PSMA-PET/CT. The primary end point was progression free survival (PFS), with disease progression defined as occurrence of either target lesion progression, new metastatic lesion or biochemical progression. Secondary outcomes were biochemical PFS (BPFS), ADT-free survival (ADT-FS), toxicity and quality of life (QoL). Baseline patient characteristics were tested for association with PFS and a preliminary risk score was created. RESULTS: Median follow-up was 21 months (interquartile range 10-31 months). Median PFS and BPFS were 16 and 21 months, respectively. Median ADT-FS was not reached (73% (95%-CI 62-86%) at 24 months). In multivariable analysis, younger age, higher PSA prior to SBRT and extrapelvic location were associated with shorter PFS. Grade 1 fatigue was the most predominant acute toxicity (34%). Highest grade toxicity was grade 2 for acute and late events. QoL analysis showed mild, transient increase in fatigue at 1-4 weeks after SBRT. CONCLUSION: A median PFS of 16 months was attained after SBRT for patients with PSMA-PET positive oligometastatic lymph nodes from prostate cancer. Higher pre-SBRT PSA, younger age and extrapelvic location were found to be predictors of shorter PFS

Upstaging by para-aortic lymph node dissection in patients with locally advanced cervical cancer: A systematic review and meta-analysis

Background: Accurate staging of para-aortic nodal status in cervical cancer is of great importance for individualizing treatment and impacting outcomes. Three-dimensional imaging (i.e. PET, CT, MRI) may miss para-aortic lymph node (PALN) metastases. The aim of this study was to systematically review and meta-analyze the proportion of upstaging by PALN dissection in patients with locally advanced cervical cancer without suspicious PALNs on imaging. Methods: PubMed/MEDLINE and Embase were systematically searched. The analysis included diagnostic studies that reported on 3D imaging and pre-therapeutic surgical assessment of PALN status in patients with cervical cancer. An overall pooled upstaging rate was calculated using a random-effects model. Results: The search identified 16 eligible studies including 18 cohorts with a total of 1530 patients. Pooling of 12 cohorts demonstrated an upstaging rate of 12% (95% confidence interval [CI] 10–15%) by PALN dissection after negative PET or PET-CT. Pooling of 6 cohorts demonstrated a pooled upstaging rate of 11% (95% CI: 8–16%) by PALN dissection after negative MRI or CT. No significant heterogeneity in upstaging proportions across cohorts was observed (I2 = 0% and 27%, respectively). In 7 cohorts including only patients with pelvic nodal metastases on imaging (but no suspicion of PALN involvement) a pooled upstaging rate by PALN dissection of 21% (95% CI: 17–26%) was found (I2 = 0%). Conclusions: This meta-analysis demonstrates that in case of no suspicious PALN on PET-CT or MRI, PALN dissection still identifies lymph node metastases in a considerable amount of patients with locally advanced cervical cancer and especially in those patients with confirmed pelvic nodal metastases

The impact of para-aortic lymph node irradiation on disease-free survival in patients with cervical cancer: A systematic review and meta-analysis

Background: Patients with locally advanced cervical cancer without para-aortic lymph node metastases (PAO-LNM) at diagnosis who undergo concurrent chemoradiotherapy are at 4-11% risk of developing PAO-LNM during follow-up. Some studies suggest a beneficial influence of elective para-aortic radiotherapy (PAO-RT) on disease-free survival (DFS) in these patients. The aim of this study was to systematically review and meta-analyse literature on the impact of PAO-RT on DFS in cervical cancer patients. Methods: A systematic search of PubMed/MEDLINE and EMBASE databases was performed. The analysis included intervention studies that reported on DFS in patients with cervical cancer who received chemotherapy and pelvic radiotherapy with or without PAO-RT. From each included study, relevant study characteristics and outcome data including the hazard ratio (HR) adjusted for potential confounders were extracted. An overall pooled adjusted hazard ratio (aHR) for DFS after PAO-RT versus no PAO-RT was calculated using a random-effects model. Results: A total of 2,016 articles were evaluated. Eleven articles were included in the systematic review, of which 3 were appropriate for quantitative meta-analysis. Pooling of these 3 cohorts (including 1,113 patients) demonstrated a statistically significant association between PAO-RT and DFS (pooled aHR 0.87, 95% confidence interval: 0.79-0.97). No significant heterogeneity among reported aHRs was observed (I 2 = 0.0%). Conclusions: This meta-analysis suggests a modest but significant beneficial impact of elective para-aortic radiotherapy on DFS in patients with locally advanced cervical cancer who undergo concurrent chemoradiotherapy. This finding based on non-randomized studies provides an imperative for further investigation in prospective controlled trials

Automated causal inference in application to randomized controlled clinical trials

Randomized controlled trials (RCTs) are considered the gold standard for testing causal hypotheses in the clinical domain; however, the investigation of prognostic variables of patient outcome in a hypothesized cause–effect route is not feasible using standard statistical methods. Here we propose a new automated causal inference method (AutoCI) built on the invariant causal prediction (ICP) framework for the causal reinterpretation of clinical trial data. Compared with existing methods, we show that the proposed AutoCI allows one to clearly determine the causal variables of two real-world RCTs of patients with endometrial cancer with mature outcome and extensive clinicopathological and molecular data. This is achieved via suppressing the causal probability of non-causal variables by a wide margin. In ablation studies, we further demonstrate that the assignment of causal probabilities by AutoCI remains consistent in the presence of confounders. In conclusion, these results confirm the robustness and feasibility of AutoCI for future applications in real-world clinical analysis

Fluorescent Indocyanine Green versus Technetium-99m and Blue Dye for Bilateral SENTinel Lymph Node Detection in Stage I-IIA Cervical Cancer (FluoreSENT): protocol for a non-inferiority study

INTRODUCTION: Nowadays, two predominant methods for detecting sentinel lymph nodes (SLNs) in cervical cancer are in use. The most conventional method is a combination of a radiotracer, technetium-99m ( 99mTc) and blue dye. More recently, another method for SLN mapping using indocyanine green (ICG) is becoming widely accepted. ICG is a fluorescent dye, visualised intraoperatively with near-infrared (NIR) fluorescence imaging, providing real-time visual navigation. The presumed advantages of ICG over 99mTc, that is, being cheaper, non-radioactive and logistically more attractive, are only valuable if its detection rate proves to be at least non-inferior. Before omitting the well-functioning and evidence-based combined approach of 99mTc and blue dye, we aim to provide prospective evidence on the non-inferiority of ICG with NIR fluorescence imaging. METHODS AND ANALYSIS: We initiated a prospective non-inferiority study with a paired comparison of both SLN methods in a single sample of 101 patients with International Federation of Gynecology and Obstetrics (FIGO) stage IA-IB2 or IIA1 cervical cancer receiving primary surgical treatment. All patients undergo SLN mapping with ICG and NIR fluorescence imaging in adjunct to mapping with 99mTc (including single photon emission computed tomography with X-ray computed tomography (SPECT/CT)) and blue dye. Surgeons start SLN detection with ICG while being blinded for the preoperative outcome of SPECT/CT to avoid biased detection with ICG. Primary endpoint of this study is bilateral SLN detection rate of both methods (ie, detection of at least one SLN in each hemipelvis). Since we compare strategies for SLN mapping that are already applied in current daily practice for different types of cancer, no additional risks or burdens are expected from these study procedures. ETHICS AND DISSEMINATION: The current study is approved by the Medical Ethics Research Committee Utrecht (reference number 21-014). Findings arising from this study will be disseminated in peer-reviewed journals, academic conferences and through patient organisations. TRIAL REGISTRATION NUMBER: NL9011 and EudraCT 2020-005134-15

Prognostic Significance of POLE Proofreading Mutations in Endometrial Cancer

Background: Current risk stratification in endometrial cancer (EC) results in frequent over- and underuse of adjuvant therapy, and may be improved by novel biomarkers. We examined whether POLE proofreading mutations, recently reported in about 7% of ECs, predict prognosis. Methods: We performed targeted POLE sequencing in ECs from the PORTEC-1 and -2 trials (n = 788), and analyzed clinical outcome according to POLE status. We combined these results with those from three additional series (n = 628) by meta-analysis to generate multivariable-adjusted, pooled hazard ratios (HRs) for recurrence-free survival (RFS) and cancer-specific survival (CSS) of POLE-mutant ECs. All statistical tests were two-sided. Results: POLE mutations were detected in 48 of 788 (6.1%) ECs from PORTEC-1 and-2 and were associated with high tumor grade (P < .001). Women with POLE-mutant ECs had fewer recurrences (6.2% vs 14.1%) and EC deaths (2.3% vs 9.7%), though, in the total PORTEC cohort, differences in RFS and CSS were not statistically significant (multivariable-adjusted HR = 0.43, 95% CI = 0.13 to 1.37, P = .15; HR = 0.19, 95% CI = 0.03 to 1.44, P = .11 respectively). However, of 109 grade 3 tumors, 0 of 15 POLE-mutant ECs recurred, compared with 29 of 94 (30.9%) POLE wild-type cancers; reflected in statistically significantly greater RFS (multivariable-adjusted HR = 0.11, 95% CI = 0.001 to 0.84, P = .03). In the additional series, there were no EC-related events in any of 33 POLE-mutant ECs, resulting in a multivariable-adjusted, pooled HR of 0.33 for RFS (95% CI = 0.12 to 0.91, P = .03) and 0.26 for CSS (95% CI = 0.06 to 1.08, P = .06). Conclusion: POLE proofreading mutations predict favorable EC prognosis, independently of other clinicopathological variables, with the greatest effect seen in high-grade tumors. This novel biomarker may help to reduce overtreatment in E