Background: The angiosome concept is defined as the anatomical territory of a source artery within all tissue layers. When applying this theory in vascular surgery, direct revascularization (DR) is... Show moreBackground: The angiosome concept is defined as the anatomical territory of a source artery within all tissue layers. When applying this theory in vascular surgery, direct revascularization (DR) is preferred to achieve increased blood flow toward the targeted angiosome of the foot in patients with lower extremity arterial disease (LEAD). This study evaluates the applicability of the angiosome concept using quantified near-infrared (NIR) fluorescence imaging with indocMethods: This study included patients undergoing an endovascular- or surgical revascularization of the leg between January 2019 and December 2021. Preinterventional and postinterventional ICG NIR fluorescence imaging was performed. Three angiosomes on the dorsum of the foot were determined: the posterior tibial artery (hallux), the anterior tibial artery (dorsum of the foot) and the combined angiosome (second to fifth digit). The angiosomes were classified from the electronic patient records and the degree of collateralization was classified based on preprocedural computed tomography angiography and/or X-ray angiography. Fluorescence intensity was quantified in all angiosomes. A subgroup analysis based on endovascular or surgical revascularized angiosomes, and within critical limb threatening ischemia (CLTI) patients was performed. Results: ICG NIR fluorescence measurements were obtained in 52 patients (54 limbs) including a total of 157 angiosomes (121 DR and 36 indirect revascularizations [IR]). A significant improvement of all perfusion parameters in both the directly and indirectly revascularized angiosomes was found (P-values between <0.001e0.007). Within the indirectly revascularized angiosomes, 90.6% of the scored collaterals were classified as significant. When comparing the percentual change in perfusion parameters between the directly and indirectly revascularized angiosomes, no significant difference was seen in all perfusion parameters (P-values between 0.253 and 0.881). Similar results were shown in the CLTI patients subgroup analysis, displaying a significant improvement of perfusion parameters in both the direct and indirect angiosome groups (P-values between <0.001 and 0.007), and no significant difference when comparing the percentual parameter improvement between both angiosome groups (P-values between 0.134 and 0.359). Furthermore, no significant differences were observed when comparing Show less
Warmerdam, B.W.C.M.; Stevens, M.; Rijswijk, C.S.P. van; Eefting, D.; Meer, R.W. van der; Putter, H.; ... ; Schaik, J. van 2023
Background: When introducing new techniques, attention must be paid to learning curve. Be-sides quantitative outcomes, qualitative factors of influence should be taken into consideration. This... Show moreBackground: When introducing new techniques, attention must be paid to learning curve. Be-sides quantitative outcomes, qualitative factors of influence should be taken into consideration. This retrospective cohort study describes the quantitative learning curve of complex endovascu-lar aortic repair (EVAR) in a nonhigh-volume academic center and provides qualitative factors that were perceived as contributors to this learning curve. With these factors, we aim to aid in future implementation of new techniques. Methods: All patients undergoing complex EVAR in the Leiden University Medical Center (LUMC) between July 2013 and April 2021 were included (n = 90). Quantitative outcomes were as follows: operating time, blood loss, volume of contrast, hospital stay, major adverse events (MAE), 30-day mortality, and complexity. Patients were divided into 3 temporal groups (n = 30) for dichotomous outcomes. Regression plots were used for continuous outcomes. In 2017, the treatment team was interviewed by an external researcher. These interviews were reanalyzed for factors that contributed to successful implementation. Results: Length of hospital stay (P = 0.008) and operating time (P = 0.010) decreased signif-icantly over time. Fewer cardiac complications occurred in the third group (3: 0% vs. 2: 17% vs. 1: 17%, P = 0.042). There was a trend of increasing complexity (P = 0.076) and number of fen-estrations (P = 0.060). No significant changes occurred in MAE and 30-day mortality. Qualitative factors that, according to the interviewees, positively influenced the learning curve were as fol-lows: communication, mutual trust, a shared sense of responsibility and collective goals, clear authoritative structures, mutual learning, and team capabilities. Conclusions: In addition to factors previously identified in the literature, new learning curve factors were found (mutual learning and shared goals in the operating room (OR)) that should be taken into account when implementing new techniques. Show less
Hematopoietic stem cell transplantation is a high-risk procedure. Auditing and yearly outcome reviews help keep optimal quality of care and come with increased survival, but also has significant... Show moreHematopoietic stem cell transplantation is a high-risk procedure. Auditing and yearly outcome reviews help keep optimal quality of care and come with increased survival, but also has significant recurring costs. When data has been entered in a standardized registry, outcome analyses can be automated, which reduces work and increases standardization of performed analyses. To achieve this, we created the Yearly Outcome Review Tool (YORT), an offline, graphical tool that gets data from a single center EBMT registry export, allows the user to define filters and groups, and performs standardized analyses for overall survival, event-free survival, engraftment, relapse rate and non-relapse mortality, complications including acute and chronic Graft vs Host Disease (GvHD), and data completeness. YORT allows users to export data as analyzed to allow you to check data and perform manual analyses. We show the use of this tool on a two-year single-center pediatric cohort, demonstrating how the results for both overall and event-free survival and engraftment can be visualized. The current work demonstrates that using registry data, standardized tools can be made to analyze this data, which allows users to perform outcome reviews for local and accreditation purposes graphically with minimal effort, and help perform detailed standardized analyses. The tool is extensible to be able to accommodate future changes in outcome review and center-specific extensions. Show less
Bonneville, E.F.; Schetelig, J.; Putter, H.; Wreede, L.C. de 2023
Missing data are frequently encountered across studies in clinical haematology. Failure to handle these missing values in an appropriate manner can complicate the interpretation of a study's... Show moreMissing data are frequently encountered across studies in clinical haematology. Failure to handle these missing values in an appropriate manner can complicate the interpretation of a study's findings, as estimates presented may be biased and/or imprecise. In the present work, we first provide an overview of current methods for handling missing covariate data, along with their advantages and disadvantages. Furthermore, a systematic review is presented, exploring both contemporary reporting of missing values in major haematological journals, and the methods used for handling them. A principal finding was that the method of handling missing data was explicitly specified in a minority of articles (in 76 out of 195 articles reporting missing values, 39%). Among these, complete case analysis and the missing indicator method were the most common approaches to dealing with missing values, with more complex methods such as multiple imputation being extremely rare (in 7 out of 195 articles). An example analysis (with associated code) is also provided using hematopoietic stem cell transplantation data, illustrating the different approaches to handling missing values. We conclude with various recommendations regarding the reporting and handling of missing values for future studies in clinical haematology. Show less
Background Prediction models for risk of cardiovascular events generally do not include young adults, and cardiovascular risk factors differ between women and men. Therefore, this study aimed to... Show moreBackground Prediction models for risk of cardiovascular events generally do not include young adults, and cardiovascular risk factors differ between women and men. Therefore, this study aimed to develop prediction models for first-ever cardiovascular event risk in men and women aged 30 to 49 years.Methods and Results We included patients aged 30 to 49 years without cardiovascular disease from a Dutch routine care database. Outcome was defined as first-ever cardiovascular event. Our reference models were sex-specific Cox proportional hazards models based on traditional cardiovascular predictors, which we compared with models using 2 predictor subsets with the 20 or 50 most important predictors based on the Cox elastic net model regularization coefficients. We assessed the C-index and calibration curve slopes at 10 years of follow-up. We stratified our analyses based on 30- to 39-year and 40- to 49-year age groups at baseline. We included 542 141 patients (mean age 39.7, 51% women). During follow-up, 10 767 cardiovascular events occurred. Discrimination of reference models including traditional cardiovascular predictors was moderate (women: C-index, 0.648 [95% CI, 0.645-0.652]; men: C-index, 0.661 [95%CI, 0.658-0.664]). In women and men, the Cox proportional hazard models including 50 most important predictors resulted in an increase in C-index (0.030 and 0.012, respectively), and a net correct reclassification of 3.7% of the events in women and 1.2% in men compared with the reference model.Conclusions Sex-specific electronic health record-derived prediction models for first-ever cardiovascular events in the general population aged <50 years have moderate discriminatory performance. Data-driven predictor selection leads to identification of nontraditional cardiovascular predictors, which modestly increase performance of models. Show less
BackgroundPrediction models for risk of cardiovascular events generally do not include young adults, and cardiovascular risk factors differ between women and men. Therefore, this study aimed to... Show moreBackgroundPrediction models for risk of cardiovascular events generally do not include young adults, and cardiovascular risk factors differ between women and men. Therefore, this study aimed to develop prediction models for first‐ever cardiovascular event risk in men and women aged 30 to 49 years.Methods and ResultsWe included patients aged 30 to 49 years without cardiovascular disease from a Dutch routine care database. Outcome was defined as first‐ever cardiovascular event. Our reference models were sex‐specific Cox proportional hazards models based on traditional cardiovascular predictors, which we compared with models using 2 predictor subsets with the 20 or 50 most important predictors based on the Cox elastic net model regularization coefficients. We assessed the C‐index and calibration curve slopes at 10 years of follow‐up. We stratified our analyses based on 30‐ to 39‐year and 40‐ to 49‐year age groups at baseline. We included 542 141 patients (mean age 39.7, 51% women). During follow‐up, 10 767 cardiovascular events occurred. Discrimination of reference models including traditional cardiovascular predictors was moderate (women: C‐index, 0.648 [95% CI, 0.645–0.652]; men: C‐index, 0.661 [95%CI, 0.658–0.664]). In women and men, the Cox proportional hazard models including 50 most important predictors resulted in an increase in C‐index (0.030 and 0.012, respectively), and a net correct reclassification of 3.7% of the events in women and 1.2% in men compared with the reference model.ConclusionsSex‐specific electronic health record‐derived prediction models for first‐ever cardiovascular events in the general population aged <50 years have moderate discriminatory performance. Data‐driven predictor selection leads to identification of nontraditional cardiovascular predictors, which modestly increase performance of models. Show less
Primary plasma cell leukemia (pPCL) is a rare and challenging malignancy. There are limited data regarding optimum transplant approaches. We therefore undertook a retrospective analysis from 1998... Show morePrimary plasma cell leukemia (pPCL) is a rare and challenging malignancy. There are limited data regarding optimum transplant approaches. We therefore undertook a retrospective analysis from 1998-2014 of 751 patients with pPCL undergoing one of four transplant strategies; single autologous transplant (single auto), single allogeneic transplant (allo-first) or a combined tandem approach with an allogeneic transplant following an autologous transplant (auto-allo) or a tandem autologous transplant (auto-auto). To avoid time bias, multiple analytic approaches were employed including Cox models with time-dependent covariates and dynamic prediction by landmarking. Initial comparisons were made between patients undergoing allo-first (n=70) versus auto -first (n=681), regardless of a subsequent second transplant. The allo-first group had a lower relapse rate (45.9%, 95% confidence interval [95% CI]: 33.2-58.6 vs. 68.4%, 64.4-72.4) but higher non -relapse mortality (27%, 95% CI: 15.9-38.1 vs. 7.3%, 5.2-9.4) at 36 months. Patients who underwent allo-first had a remarkably higher risk in the first 100 days for both overall survival and progression-free survival. Patients undergoing auto-allo (n=122) had no increased risk in the short term and a significant benefit in progression-free survival after 100 days compared to those undergoing single auto (hazard ratio [HR]=0.69, 95% CI: 0.52-0.92; P=0.012). Auto-auto (n=117) was an effective option for patients achieving complete remission prior to their first transplant, whereas in patients who did not achieve complete remission prior to transplantation our modeling predicted that auto-allo was superior. This is the largest retrospective study reporting on transplantation in pPCL to date. We confirm a significant mortality risk within the first 100 days for allo-first and suggest that tandem transplant strategies are superior. Disease status at time of transplant influences outcome. This knowledge may help to guide clinical decisions on transplant strategy. Show less
IntroductionAlthough optimising rectal cancer treatment has reduced local recurrence rates, many patients develop distant metastases (DM). The current study investigated whether a total neoadjuvant...Show moreIntroductionAlthough optimising rectal cancer treatment has reduced local recurrence rates, many patients develop distant metastases (DM). The current study investigated whether a total neoadjuvant treatment strategy influences the development, location, and timing of metastasesin patients diagnosed with high-risk locally advanced rectal cancer included in the Rectal cancer And Pre-operative Induction therapy followed by Dedicated Operation (RAPIDO) trial.Material and methodsPatients were randomly assigned to short-course radiotherapy followed by 18 weeks of CAPOX or FOLFOX4 before surgery (EXP), or long-course chemoradiotherapy with optional postoperative chemotherapy (SC-G). Assessments for metastatic disease were performed pre- and post-treatment, during surgery, and 6, 12, 24, 36, and 60 months postoperatively. From randomisation, differences in the occurrence of DM and first site of metastasis were evaluated.ResultsIn total, 462 patients were evaluated in the EXP and 450 patients in the SC-G groups. The cumulative probability of DM at 5 years after randomisation was 23% [95% CI 19–27] and 30% [95% CI 26–35] (HR 0.72 [95% CI 0.56–0.93]; P = 0.011) in the EXP and SC-G, respectively. The median time to DM was 1.4 (EXP) and 1.3 years (SC-G). After diagnosis of DM, median survival was 2.6 years [95% CI 2.0–3.1] in the EXP and 3.2 years [95% CI 2.3–4.1] in the SC-G groups (HR 1.39 [95% CI 1.01–1.92]; P = 0.04). First occurrence of DM was most often in the lungs (60/462 [13%] EXP and 55/450 [12%] SC-G) or the liver (40/462 [9%] EXP and 69/450 [15%] SC-G). A hospital policy of postoperative chemotherapy did not influence the development of DM.ConclusionsCompared to long-course chemoradiotherapy, total neoadjuvant treatment with short-course radiotherapy and chemotherapy significantly decreased the occurrence of metastases, particularly liver metastases. Show less
From 2016 EBMT and JACIE developed an international risk-adapted benchmarking program of haematopoietic stem cell transplant (HSCT) outcome to provide individual EBMT Centers with a means of... Show moreFrom 2016 EBMT and JACIE developed an international risk-adapted benchmarking program of haematopoietic stem cell transplant (HSCT) outcome to provide individual EBMT Centers with a means of quality-assuring the HSCT process and meeting FACT-JACIE accreditation requirements relating to 1-year survival outcomes. Informed by previous experience from Europe, North America and Australasia, the Clinical Outcomes Group (COG) established criteria for patient and Center selection, and a set of key clinical variables within a dedicated statistical model adapted to the capabilities of the EBMT Registry. The first phase of the project was launched in 2019 to test the acceptability of the benchmarking model through assessment of Centers' performance for 1-year data completeness and survival outcomes of autologous and allogeneic HSCT covering 2013-2016. A second phase was delivered in July 2021 covering 2015-2019 and including survival outcomes. Reports of individual Center performance were shared directly with local principal investigators and their responses were assimilated. The experience thus far has supported the feasibility, acceptability and reliability of the system as well as identifying its limitations. We provide a summary of experience and learning so far in this 'work in progress', as well as highlighting future challenges of delivering a modern, robust, data-complete, risk-adapted benchmarking program across new EBMT Registry systems. Show less
BackgroundPre-operative chemoradiotherapy (CRT) rather than radiotherapy (RT) has resulted in fewer locoregional recurrences (LRRs), but no decrease in distant metastasis (DM) rate for patients... Show moreBackgroundPre-operative chemoradiotherapy (CRT) rather than radiotherapy (RT) has resulted in fewer locoregional recurrences (LRRs), but no decrease in distant metastasis (DM) rate for patients with locally advanced rectal cancer (LARC). In many countries, patients receive post-operative chemotherapy (pCT) to improve oncological outcomes. We investigated the value of pCT after pre-operative CRT in the RAPIDO trial.Patients and methodsPatients were randomised between experimental (short-course RT, chemotherapy and surgery) and standard-of-care treatment (CRT, surgery and pCT depending on hospital policy). In this substudy, we compared curatively resected patients from the standard-of-care group who received pCT (pCT+ group) with those who did not (pCT− group). Subsequently, patients from the pCT+ group who received at least 75% of the prescribed chemotherapy cycles (pCT ≥75% group) were compared with patients who did not receive pCT (pCT−/− group). By propensity score stratification (PSS), we adjusted for the following unbalanced confounders: age, clinical extramural vascular invasion, distance to the anal verge, ypT stage, ypN stage, residual tumour, serious adverse event (SAE) and/or readmission within 6 weeks after surgery and SAE related to pre-operative CRT. Cumulative probability of disease-free survival (DFS), DM, LRR and overall survival (OS) was analysed by Cox regression.ResultsIn total, 396/452 patients had a curative resection. The number of patients in the pCT+, pCT >75%, pCT− and pCT−/− groups was 184, 112, 154 and 149, respectively. The PSS-adjusted analyses for all endpoints demonstrated hazard ratios between approximately 0.7 and 0.8 (pCT+ versus pCT−), and 0.5 and 0.8 (pCT ≥75% versus pCT−/−). However, all 95% confidence intervals included 1.ConclusionsThese data suggest a benefit of pCT after pre-operative CRT for patients with high-risk LARC, with approximately 20%-25% improvement in DFS and OS and 20%-25% risk reductions in DM and LRR. Compliance with pCT additionally reduces or improves all endpoints by 10%-20%. However, differences are not statistically significant. Show less
Kantidakis, G.; Putter, H.; Litière, S.; Fiocco, M. 2023
BackgroundIn health research, several chronic diseases are susceptible to competing risks (CRs). Initially, statistical models (SM) were developed to estimate the cumulative incidence of an event... Show moreBackgroundIn health research, several chronic diseases are susceptible to competing risks (CRs). Initially, statistical models (SM) were developed to estimate the cumulative incidence of an event in the presence of CRs. As recently there is a growing interest in applying machine learning (ML) for clinical prediction, these techniques have also been extended to model CRs but literature is limited. Here, our aim is to investigate the potential role of ML versus SM for CRs within non-complex data (small/medium sample size, low dimensional setting).MethodsA dataset with 3826 retrospectively collected patients with extremity soft-tissue sarcoma (eSTS) and nine predictors is used to evaluate model-predictive performance in terms of discrimination and calibration. Two SM (cause-specific Cox, Fine-Gray) and three ML techniques are compared for CRs in a simple clinical setting. ML models include an original partial logistic artificial neural network for CRs (PLANNCR original), a PLANNCR with novel specifications in terms of architecture (PLANNCR extended), and a random survival forest for CRs (RSFCR). The clinical endpoint is the time in years between surgery and disease progression (event of interest) or death (competing event). Time points of interest are 2, 5, and 10 years.ResultsBased on the original eSTS data, 100 bootstrapped training datasets are drawn. Performance of the final models is assessed on validation data (left out samples) by employing as measures the Brier score and the Area Under the Curve (AUC) with CRs. Miscalibration (absolute accuracy error) is also estimated. Results show that the ML models are able to reach a comparable performance versus the SM at 2, 5, and 10 years regarding both Brier score and AUC (95% confidence intervals overlapped). However, the SM are frequently better calibrated.ConclusionsOverall, ML techniques are less practical as they require substantial implementation time (data preprocessing, hyperparameter tuning, computational intensity), whereas regression methods can perform well without the additional workload of model training. As such, for non-complex real life survival data, these techniques should only be applied complementary to SM as exploratory tools of model's performance. More attention to model calibration is urgently needed. Show less
Multi-state models are used to describe how individuals transition through different states over time. The distribution of the time spent in different states, referred to as 'length of stay', is... Show moreMulti-state models are used to describe how individuals transition through different states over time. The distribution of the time spent in different states, referred to as 'length of stay', is often of interest. Methods for estimating expected length of stay in a given state are well established. The focus of this paper is on the distribution of the time spent in different states conditional on the complete pathway taken through the states, which we call 'conditional length of stay'. This work is motivated by questions about length of stay in hospital wards and intensive care units among patients hospitalised due to Covid-19. Conditional length of stay estimates are useful as a way of summarising individuals' transitions through the multi-state model, and also as inputs to mathematical models used in planning hospital capacity requirements. We describe non-parametric methods for estimating conditional length of stay distributions in a multi-state model in the presence of censoring, including conditional expected length of stay (CELOS). Methods are described for an illness-death model and then for the more complex motivating example. The methods are assessed using a simulation study and shown to give unbiased estimates of CELOS, whereas naive estimates of CELOS based on empirical averages are biased in the presence of censoring. The methods are applied to estimate conditional length of stay distributions for individuals hospitalised due to Covid-19 in the UK, using data on 42,980 individuals hospitalised from March to July 2020 from the COVID19 Clinical Information Network. Show less
Unobserved individual heterogeneity is a common challenge in population cancer survival studies. This heterogeneity is usually associated with the combination of model misspecification and the... Show moreUnobserved individual heterogeneity is a common challenge in population cancer survival studies. This heterogeneity is usually associated with the combination of model misspecification and the failure to record truly relevant variables. We investigate the effects of unobserved individual heterogeneity in the context of excess hazard models, one of the main tools in cancer epidemiology. We propose an individual excess hazard frailty model to account for individual heterogeneity. This represents an extension of frailty modeling to the relative survival framework. In order to facilitate the inference on the parameters of the proposed model, we select frailty distributions which produce closed-form expressions of the marginal hazard and survival functions. The resulting model allows for an intuitive interpretation, in which the frailties induce a selection of the healthier individuals among survivors. We model the excess hazard using a flexible parametric model with a general hazard structure which facilitates the inclusion of time-dependent effects. We illustrate the performance of the proposed methodology through a simulation study. We present a real-data example using data from lung cancer patients diagnosed in England, and discuss the impact of not accounting for unobserved heterogeneity on the estimation of net survival. The methodology is implemented in the R package IFNS. Show less
Suvaal, I.; Kirchheiner, K.; Nout, R.A.; Sturdza, A.E.; Limbergen, E. van; Lindegaard, J.C.; ... ; Kuile, M.M. ter 2023
Objective. The EMBRACE-vaginal morbidity substudy prospectively evaluated physician-assessed vaginal changes and patient-reported-outcomes (PRO) on vaginal and sexual functioning problems and... Show moreObjective. The EMBRACE-vaginal morbidity substudy prospectively evaluated physician-assessed vaginal changes and patient-reported-outcomes (PRO) on vaginal and sexual functioning problems and distress in the first 2-years after image-guided radio(chemo)therapy and brachytherapy for locally advanced cervical cancer.Methods. Eligible patients had stage IB1-IIIB cervical cancer with <= 5 mm vaginal involvement. Assessment of vaginal changes was graded using CTCAE. PRO were assessed using validated Quality-of-Life and sexual question-naires. Statistical analysis included Generalized-Linear-Mixed-Models and Spearman's rho-correlation coeffi-cients.Results. 113 eligible patients were included. Mostly mild (grade 1) vaginal changes were reported over time in about 20% (range 11-37%). At 2-years, 47% was not sexually active. Approximately 50% of the sexually active women reported any vaginal and sexual functioning problems and distress over time; more substantial vaginal and sexual problems and distress were reported by up to 14%, 20% and 8%, respectively. Physician-assessed vag-inal changes and PRO sexual satisfaction differed significantly (p <=.05) between baseline and first follow-up, without further significant changes over time. No or only small associations between physician-assessed vaginal changes and PRO vaginal functioning problems and sexual distress were found.Conclusions. Mild vaginal changes were reported after image-guided radio(chemo)therapy and brachyther-apy, potentially due to the combination of tumors with limited vaginal involvement, EMBRACE-specific treatment optimization and rehabilitation recommendations. Although vaginal and sexual functioning problems and sexual distress were frequently reported, the rate of substantial problems and distress was low. The lack of association between vaginal changes, vaginal functioning problems and sexual distress shows that sexual functioning is more complex than vaginal morbidity alone.(c) 2023 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http:// creativecommons.org/licenses/by/4.0/). Show less
Bohnstedt, M.; Gampe, J.; Caljouw, M.A.A.; Putter, H. 2023
In studies of recurrent events, joint modeling approaches are often needed to allow for potential dependent censoring by a terminal event such as death. Joint frailty models for recurrent events... Show moreIn studies of recurrent events, joint modeling approaches are often needed to allow for potential dependent censoring by a terminal event such as death. Joint frailty models for recurrent events and death with an additional dependence parameter have been studied for cases in which individuals are observed from the start of the event processes. However, samples are often selected at a later time, which results in delayed entry so that only individuals who have not yet experienced the terminal event will be included. In joint frailty models such left truncation has effects on the frailty distribution that need to be accounted for in both the recurrence process and the terminal event process, if the two are associated. We demonstrate, in a comprehensive simulation study, the effects that not adjusting for late entry can have and derive the correctly adjusted marginal likelihood, which can be expressed as a ratio of two integrals over the frailty distribution. We extend the estimation method of Liu and Huang (Stat Med 27:2665-2683, 2008.) to include potential left truncation. Numerical integration is performed by Gaussian quadrature, the baseline intensities are specified as piecewise constant functions, potential covariates are assumed to have multiplicative effects on the intensities. We apply the method to estimate age-specific intensities of recurrent urinary tract infections and mortality in an older population. Show less
Background Chronic anal fissure is a common benign anorectal disease with a high recurrence rate. Pelvic floor physical therapy has been proven effective in the short-term management in patients... Show moreBackground Chronic anal fissure is a common benign anorectal disease with a high recurrence rate. Pelvic floor physical therapy has been proven effective in the short-term management in patients with chronic anal fissure and pelvic floor dysfunction (PAF-trial). The aim of this study was to determine the outcomes of the PAF-trial and fissure recurrence in patients who completed the 2 months of pelvic floor physical therapy at 1-year follow-up.Methods Electromyographic registration of the pelvic floor, digital rectal examination, visual analog scales, patient-related outcome measurements, and quality of life were assessed at baseline and at 1-year after inclusion. The primary outcome was muscle tone at rest during electromyographic registration of the pelvic floor at baseline and at 1-year follow-up. Secondary outcomes contained fissure recurrence, pain ratings, pelvic floor dysfunction, complaint reduction measured with a proctology specific patient-reported outcome measurement, and quality of life.Results The treatment protocol was followed by 133 patients. Ninety-seven patients (71%) completed the 1-year follow-up, 48 women (49.5%) and 49 men (50.5%) with a mean age of 44.4 +/- 11.6 years (range 19-68). In the total group of patients, mean resting electromyographic values of the pelvic floor significantly improved from baseline to follow-up at 1 year (mean estimated difference 2.20 mu V; 95% CI, 1.79 to 2.61; p < 0.001). After 1 year, the fissure recurred in 15 patients (15.5%). VAS-pain significantly decreased from baseline to follow-up (mean estimated difference 4.16; 95% CI, 3.75 to 4.58; p < 0.001). Dyssynergia was found in 72.9% at baseline and decreased to 14.4% at 1-year follow-up (p < 0.001). Complaint reduction measured with the Proctoprom significantly improved from baseline to 1-year follow-up (p < 0.001). Quality of life (RAND-36) significantly improved in eight of nine domains at 1-year follow-up. No significant improvement was found in the domain vitality.Conclusions In the PAF-trial, we demonstrated that pelvic floor physical therapy yields a significant and clinical benefit in the time course and therefore should be advocated as adjuvant conservative treatment in patients with chronic anal fissure. Show less
Background: The endometrial cancer molecular classification has been integrated into the 2020 World Health Organization (WHO) diagnostic classification and European treatment guidelines, and... Show moreBackground: The endometrial cancer molecular classification has been integrated into the 2020 World Health Organization (WHO) diagnostic classification and European treatment guidelines, and provides direction towards more effective and less toxic adjuvant treatment strategies for women with endometrial cancer. Primary objective(s): The RAINBO program of clinical trials will investigate four molecular class-directed adjuvant treatment strategies following surgical resection to either increase cure rates through the addition of novel targeted therapies or safely reduce toxicity and improve quality of life through treatment de-escalation. Study hypothesis: Molecular-directed adjuvant treatment strategies will improve clinical outcomes and reduce toxicity of unwarranted therapies in women with endometrial cancer. The overarching and translational research RAINBO program will advance knowledge of predictive and prognostic (bio)markers that will improve prognostication and treatment allocation. Trial design: The RAINBO program is a platform of four international clinical trials and an overarching research program. The randomized phase III p53abn-RED trial for women with invasive stage I-III p53abn endometrial cancer compares adjuvant chemoradiation followed by olaparib for 2 years with adjuvant chemoradiation alone. The randomized phase III MMRd-GREEN trial for women with stage II (with lymphovascular space invasion (LVSI)) or stage III mismatch repair-deficient (MMRd) endometrial cancer compares adjuvant radiotherapy with concurrent and adjuvant durvalumab for 1 year to radiotherapy alone. The randomized phase III NSMP-ORANGE trial is a treatment de-escalation trial for women with estrogen receptor positive stage II (with LVSI) or stage III no specific molecular profile (NSMP) endometrial cancer comparing radiotherapy followed by progestin for 2 years to adjuvant chemoradiation. The POLEmut-BLUE trial is a phase II trial in which the safety of de-escalation of adjuvant therapy is investigated for women with stage I-III POLEmut endometrial cancer: no adjuvant therapy for lower-risk disease and no adjuvant therapy or radiotherapy alone for higher-risk disease. The overarching RAINBO program will combine data and tumor material of all participants to perform translational research and evaluate molecular class-based adjuvant therapy in terms of efficacy, toxicity, quality of life, and cost-utility. Major inclusion/exclusion criteria: Inclusion criteria include a histologically confirmed diagnosis of endometrial cancer treated by hysterectomy and bilateral salpingo-oophorectomy with or without lymphadenectomy or sentinel lymph node biopsy, with no macroscopic residual disease after surgery and no distant metastases, and molecular classification according to the WHO 2020 algorithm. Primary endpoint(s): Recurrence-free survival at 3 years in the p53abn-RED, MMRd-GREEN, and NSMP-ORANGE trials and pelvic recurrence at 3 years in the POLEmut-BLUE trial. Sample size: The p53abn-RED trial will include 554 patients, the MMRd-GREEN trial 316, the NSMP-ORANGE trial 600, and the POLEmut-BLUE trial 145 (120 for lower-risk disease and approximately 25 for higher-risk disease). The overarching research program will pool the four sub-trials resulting in a total sample size of around 1600. Estimated dates for completing accrual and presenting results: The four clinical trials will have different completion dates; main results are expected from 2028. Show less
Background: Chronic anal fissure is one of the most common anorectal diseases and is associated with reduced quality of life. The aim of this study was to investigate the effects of pelvic floor... Show moreBackground: Chronic anal fissure is one of the most common anorectal diseases and is associated with reduced quality of life. The aim of this study was to investigate the effects of pelvic floor physical therapy on quality of life in patients with chronic anal fissure using the Short-Form 36 Health Survey (RAND-36). Methods: Adult patients, with chronic anal fissure and concomitant pelvic floor dysfunction, such as dyssynergia and increased pelvic floor muscle tone, were recruited at the Proctos Clinic in the Netherlands, between December 2018 and July 2021 and randomly assigned to an intervention group, receiving 8 weeks of pelvic floor physical therapy or assigned to a control group receiving postponed pelvic floor physical therapy (PAF trial). Quality of life and pain ratings were outcomes of the study and were measured at 8- and 20-week follow-up. Results: One hundred patients (50 women and 50 men, median age 44.6 years [range 19-68 years]), completed the RAND-36 questionnaire and visual analog (VAS) pain scale score at admission. A significant improvement was found at 20-week follow-up in all domains of the RAND-36; physical functioning, pain, health change (p < 0.001); physical role, vitality, general health, social functioning, emotional role, mental health (p < 0.05). VAS pain was significantly reduced at 8 weeks (mean estimated difference 1.98; 95% CI 1.55-2.42, p < 0.001) and remained significant at 20-week follow-up (p < 0.001). The difference between the groups as regards change in the mean pain intensity scores at 8 weeks was 2.48 (95% CI - 3.20 to - 1.75; p < 0.001). Compared to the reference values of the general Dutch population, the patients in our study with a chronic anal fissure and pelvic floor dysfunction reported an impaired quality of life in 8 of 9 domains of the RAND-36. After treatment, significant lower scores were found in 2 out of 9 domains. Conclusions: The results of this study provide evidence that treatment by pelvic floor physical therapy improves quality of life and reduces pain, making it an important tool in management of chronic anal fissure and concomitant pelvic floor dysfunction. Show less
This study focuses on the impact of complications after rectal cancer surgery on the short-and long-term Health-related Quality of Life (HRQoL). The results show that. short-term HRQoL was affected... Show moreThis study focuses on the impact of complications after rectal cancer surgery on the short-and long-term Health-related Quality of Life (HRQoL). The results show that. short-term HRQoL was affected by complications. Twelve months postoperative HRQoL had returned to the preoperative level regardless of complications. In patients that survived 14-years, there was no effect of complications on HRQoL detected.Background: Survival for rectal cancer patients has improved over the past decades. In parallel, long-term health -related quality of life (HRQoL) is gaining interest. This study focuses on the effect of complications following rectal cancer surgery on HRQoL and survival. Methods: The TME-trial (1996-1999) randomized patients with operable rectal cancer between surgery with preoperative short-course radiotherapy and surgery. Questionnaires including the Rotter-dam Symptom Checklist were sent at 6 time points within the first 24 months and after 14 years the EORTC QLQ-C30 and EORTC QLQ-CR29 questionnaires. Differences in HRQoL and survival between patients with and without compli-cations were analyzed. Results: A total of 1207 patients were included, of which 482 (39.9%) patients experienced complications, surgical complications occurred in 177 (14.6%) patients, non-surgical complications in 197 (16.3%) and 108 patients (8.9%) had a combination of both types of complications. Three months after surgery, patients with a combination of surgical-and non-surgical complications, especially patients with anastomotic leakage, had the worst HRQoL. Twelve months postoperative HRQoL returned to a similar level as before surgery, regardless of complications. In patients who survived 14 years, no significant differences in HRQoL were seen between patients with and without complications. However, patients with complications did have lower overall survival. Conclusion: This study shows that survival and short-term HRQoL are negatively affected by complications. Twelve months after surgery HRQoL had returned to the preoperative level regardless, of complications. Also, in patients that survived 14 years, there was no effect of complications on HRQoL detected. Show less