Search

BACKGROUND: Urine poses an attractive non-invasive means for obtaining liquid biopsies for oncological diagnostics. Especially molecular analysis on urinary DNA is a rapid growing field. However, optimal and practical storage conditions that result in preservation of urinary DNA, and in particular hypermethylated DNA (hmDNA), are yet to be determined.AIM: To determine the most optimal and practical conditions for urine storage that result in adequate preservation of DNA for hmDNA analysis.METHODS: DNA yield for use in methylation analysis was determined by quantitative methylation specific PCR (qMSP) targeting the ACTB and RASSF1A genes on bisulfite modified DNA. First, DNA yield (ACTB qMSP) was determined in a pilot study on urine samples of healthy volunteers using two preservatives (Ethylenediaminetetraacetic acid (EDTA) and Urine Conditioning Buffer, Zymo Research) at four different temperatures (room temperature (RT), 4°C, -20°C, -80°C) for four time periods (1, 2, 7, 28 days). Next, hmDNA levels (RASSF1A qMSP) in stored urine samples of patients suffering from bladder cancer (n = 10) or non-small cell lung cancer (NSCLC; n = 10) were measured at day 0 and 7 upon storage with and without the addition of 40mM EDTA and/or 20 μl/ml Penicillin Streptomycin (PenStrep) at RT and 4°C.RESULTS: In the pilot study, DNA for methylation analysis was only maintained at RT upon addition of preserving agents. In urine stored at 4°C for a period of 7 days or more, the addition of either preserving agent yielded a slightly better preservation of DNA. When urine was stored at -20 °C or -80 °C for up to 28 days, DNA was retained irrespective of the addition of preserving agents. In bladder cancer and NSCLC samples stored at RT loss of DNA was significantly less if EDTA was added compared to no preserving agents (p0.99). Upon storage at 4°C, no difference in DNA preservation was found after the addition of preserving agents (p = 0.18). The preservation of methylated DNA (RASSF1A) was strongly correlated to that of unmethylated DNA (ACTB) in most cases, except when PCR values became inaccurate.CONCLUSIONS: Addition of EDTA offers an inexpensive preserving agent for urine storage at RT up to seven days allowing for reliable hmDNA analysis. To avoid bacterial overgrowth PenStrep can be added without negatively affecting DNA preservation.

Background: In a recent meta-analysis, subgroups of patients were defined that may not benefit from a single, immediate instillation with chemotherapy. This led to a change in the European Association of Urology bladder cancer guidelines. In a previous paper, our group confirmed the efficacy of an immediate instillation of mitomycin C (MMC). However, prognostic groups in that study differ from those in the meta-analysis. Therefore, we performed a reanalysis using contemporary risk groups. Objectives: To validate whether specific subgroups of patients with non–muscle-invasive bladder cancer (NMIBC) benefit from an immediate instillation with MMC. Patients and methods: All 2,243 NMIBC patients enrolled in our randomized controlled trial between 1998 and 2003 were analyzed. Treatment effect was investigated for all subgroups, including subgroups that did not benefit from an immediate instillation according to the meta-analysis. Time to recurrence was assessed using Kaplan-Meier curves and multivariable Cox regression. Differences in treatment effect between subgroups was tested using the variable treatment by covariate interactions in a Cox regression model. Results: The difference in time to recurrence was statistically significant in favor of an immediate instillation with MMC (P < 0.001) which corresponds to a 25% risk reduction (hazard ratio: 0.75, 95% confidence interval, 0.64–0.88, P < 0.001). Treatment effect of an immediate instillation with MMC did not differ significantly between any of the subgroups. Conclusions: In contrast to the recommendations in the European Association of Urology guidelines, we could not identify any subgroup of patients with NMIBC who do not benefit from an immediate instillation with MMC after transurethral resection.

132 Background: Optimal (study) treatment for patients with advanced cancer is influenced by their performance status (PS) before initiation of systemic therapy. An objective assessment of a patient’s physical function is difficult to make and is currently heavily depending on the estimation of their PS by the treating physician. Objectively measured physical activity (PA) and physical fitness (FIT) may be more predictive for survival and treatment tolerability than their PS. We hypothesize that an objective measurement may provide more accurate estimates of a patient’s physical function and thereby a better outcome of (study) treatment. Unfortunately, routine objective measurements are time consuming and costly. Therefore, we aimed to investigate the validity and reliability of smartphone measurements of PA and FIT in patients with cancer. Methods: At present, 56 ambulant patients with various types of cancer participated. Patients wore an accelerometer for 7, and an IPhone for 14 consecutive days to measure the mean number of steps per day. Patients performed a 6MWT twice with the use of an smartphone application in their home environment and once in a test environment in the hospital. To assess the validity, we calculated the intraclass correlation coefficient (ICC) between the accelerometer and the first week of the IPhone for PA, and between the 6MWT in the hospital and the home environment for FIT. To assess reliability, we calculated the ICC between the IPhone week 1 and 2 for PA, and between the first and second 6MWT in the home environment for FIT. Results: Validity was excellent for PA (ICC = 0.96,p < 0.05) and low for FIT (ICC = 0.33,p < 0.05). We found excellent reliability for PA (ICC 0.94,p < 0.05) and FIT (ICC = 0.93,p < 0.05). Conclusions: In this study we found that objective smartphone measurements of PA are valid and reliable. FIT assessments were reliable, but in its present form its validity was low. A prospective study has been initiated to investigate whether objectively measured PA and/or FIT, better predicts early trial discontinuation and survival than PS or patient-reported physical function.

Objective: To design and demonstrate a customized tool to generate histologic sections of the prostate that directly correlate with needle-based optical coherence tomography pullback measurements. Materials and Methods: A customized tool was created to hold the prostatectomy specimens during optical coherence tomography measurements and formalin fixation. Using the tool, the prostate could be sliced into slices of 4 mm thickness through the optical coherence tomography measurement trajectory. In this way, whole-mount pathology slides were produced in exactly the same location as the optical coherence tomography measurements were performed. Full 3-dimensional optical coherence tomography pullbacks were fused with the histopathology slides using the 3-dimensional imaging software AMIRA, and images were compared. Results: A radical prostatectomy was performed in a patient (age: 68 years, prostate-specific antigen: 6.0 ng/mL) with Gleason score 3 + 4 = 7 in 2/5 biopsy cores on the left side (15%) and Gleason score 3 + 4 = 7 in 1/5 biopsy cores on the right side (5%). Histopathology after radical prostatectomy showed an anterior located pT2cNx adenocarcinoma (Gleason score 3 + 4 = 7). Histopathological prostate slides were produced using the customized tool for optical coherence tomography measurements, fixation, and slicing of the prostate specimens. These slides correlated exactly with the optical coherence tomography images. Various structures, for example, Gleason 3 + 4 prostate cancer, stroma, healthy glands, and cystic atrophy with septae, could be identified both on optical coherence tomography and on the histopathological prostate slides. Conclusion: We successfully designed and applied a customized tool to process radical prostatectomy specimens to improve the coregistration of whole mount histology sections to fresh tissue optical coherence tomography pullback measurements. This technique will be crucial in validating the results of optical coherence tomography imaging studies with histology and can easily be applied in other solid tissues as well, for example, lung, kidney, breast, and liver. This will help improve the efficacy of optical coherence tomography in cancer detection and staging in solid organs.

Objective: Non-Hodgkin's lymphoma (NHL) is the most common childhood malignancy in sub-Saharan Africa. Survival rates for NHL are higher than 80% in high-income countries.This study explores treatment outcomes of children with NHL in Kenya, a sub-Saharan low-income country, and the association between health insurance status at diagnosis and treatment outcomes.Design: This was a retrospective medical records study. All children diagnosed with NHL in 2010, 2011 and 2012 were included. Data on treatment outcomes and health insurance status at diagnosis were collected.Results: Of all 63 patients with NHL, 35% abandoned treatment, 22% had progressive or relapsed disease, 14% died and 29% had event-free survival. Most patients (73%) had no health insurance at diagnosis. Treatment outcomes in children with or without health insurance at diagnosis differed significantly (p=0.005). The most likely treatment outcome in children with health insurance at diagnosis was event-free survival (53%), whereas in children without health insurance at diagnosis it was abandonment of treatment (44%). Crude HR for treatment failure was 3.1 (95% CI 1.41 to 6.60, p=0.005) for uninsured versus insured children. The event-free survival estimate was significantly higher in children with health insurance at diagnosis than in patients without health insurance at diagnosis (p=0.003). Stage of disease at diagnosis was identified as a confounder of this association (adjusted HR=2.4, 95% CI 0.95 to 6.12, p=0.063).Conclusions: Survival of children with NHL in Kenya is much lower compared with high-income countries. Abandonment of treatment is the most common cause of treatment failure. Health insurance at diagnosis was associated with better treatment outcomes and survival.

To assess diagnostic accuracy of preoperatively performed magnetic resonance (MR) imaging for detection of tumor extent in a large patient population with histopathologically proved retinoblastoma.Local ethics committee approval and informed consent were not required for retrospective review of patients' images and records. Fifty-eight eyes in 28 girls (mean age, 21 months; range, 2-59 months) and 28 boys (mean age, 24 months; range, 2-76 months) with retinoblastoma were retrospectively reviewed by one radiologist on unenhanced T1-weighted, dual-echo T2-weighted, and gadolinium-enhanced T1-weighted MR images. MR imaging parameters such as growth pattern, anterior chamber hyperintensity, and involvement of choroid, ciliary body, optic nerve, sclera, orbital fat, and pineal gland were determined. Tumor volume was measured and correlated to metastatic risk factors. Imaging and pathologic findings were compared. Statistical analysis was performed by using logistic regression with log likelihood ratio chi(2) test or Fisher exact test.Choroidal invasion was suspected with MR imaging in 21 eyes; findings were false-positive in 13 eyes and false-negative in three (73% sensitivity, 72% specificity, 72% accuracy). Anterior chamber hyperintensity on T1-weighted MR images obtained after contrast agent administration correlated well with clinical presence of reactive neovascular processes. MR imaging findings were true-positive in 21 of 32 eyes with proved prelaminar optic nerve invasion (66% sensitivity) and false-positive in one (96% specificity, 79% accuracy). Postlaminar optic nerve invasion was correctly detected in two eyes; in two other eyes, this metastatic risk factor was missed (50% sensitivity, 100% specificity, 97% accuracy). Scleral and extrascleral tumor invasion were correctly excluded in all eyes. Tumor volume was statistically associated with prelaminar optic nerve invasion (P = .001) and choroidal invasion (P = .031).MR imaging is accurate for tumor staging and detection of metastatic risk factors; detection of intraocular tumor infiltration remains difficult. Tumor volume, measured with MR imaging, was associated with prelaminar optic nerve and choroidal involvement.

OBJECTIVES: To investigate the accrual proportion and patients' reasons for not participating in the PREOPANC trial on neoadjuvant chemoradiotherapy vs. immediate surgery in resectable and borderline resectable pancreatic cancer, and to compare these patients' outcomes with those of patients who had been randomized in the trial.SUMMARY OF BACKGROUND DATA: The external validity of multicenter randomized trials in cancer treatment has been criticized for suboptimal non-representative inclusion. In trials, it is unclear how outcomes compare between randomized and non-randomized patients.METHODS: At eight of 16 participant centers, this multicenter observational study identified validation patients, who had been eligible but not randomized during recruitment for the PREOPANC trial. We assessed the accrual proportion, investigated their most common reasons for not participating in the trial, and compared resection rates, radical (R0) resection rates and overall survival (OS) between the validation patients and PREOPANC patients, who had been randomized in the trial to immediate surgery.RESULTS: In total, 455 patients had been eligible during the recruitment period, 151 of whom (33%) had been randomized. Fifty-five percent of the 304 validation patients had refused to participate. Median OS in the validation group was 15.2 months, against 15.5 months in the PREOPANC group (p = 1.00). The respective resection rates (76% vs. 73%) and R0 resection rates (51% vs. 46%) did not differ between the groups.CONCLUSIONS: The PREOPANC trial included a reasonable percentage of 33% of eligible patients. In terms of the outcomes survival, resection rate, and R0 resection rate, this appeared to be a representative group.

Background: Spatio-temporal evolution of cord atrophy in multiple sclerosis (MS) has not been investigated yet. Objective: To evaluate voxel-wise distribution and 1-year changes of cervical cord atrophy in a multicentre MS cohort. Methods: Baseline and 1-year 3D T1-weighted cervical cord scans and clinical evaluations of 54 healthy controls (HC) and 113 MS patients (14 clinically isolated syndromes (CIS), 77 relapsing-remitting (RR), 22 progressive (P)) were used to investigate voxel-wise cord volume loss in patients versus HC, 1-year volume changes and clinical correlations (SPM12). Results: MS patients exhibited baseline cord atrophy versus HC at anterior and posterior/lateral C1/C2 and C4–C6 ( p < 0.05, corrected). While CIS patients showed baseline volume increase at C4 versus HC ( p < 0.001, uncorrected), RRMS exhibited posterior/lateral C1/C2 atrophy versus CIS, and PMS showed widespread cord atrophy versus RRMS ( p < 0.05, corrected). At 1 year, 13 patients had clinically worsened. Cord atrophy progressed in MS, driven by RRMS, at posterior/lateral C2 and C3–C6 ( p < 0.05, corrected). CIS patients showed no volume changes, while PMS showed circumscribed atrophy progression. Baseline cord atrophy at posterior/lateral C1/C2 and C3–C6 correlated with concomitant and 1-year disability ( r = −0.40/–0.62, p < 0.05, corrected). Conclusions: Voxel-wise analysis characterized spinal cord neurodegeneration over 1 year across MS phenotypes and helped to explain baseline and 1-year disability.

16α-18F-fluoro-17β-estradiol (18F-FES) is a positron emission tomography (PET) tracer characterizing the expression of the estrogen receptor (ER). As therapy can interfere with the kinetics and biodistribution of 18F-FES, the aim of this study was to describe the biodistribution of 18F-FES in patients with metastatic ER+ breast cancer undergoing treatment with rintodestrant (G1T48), a novel selective ER degrader. Methods: Eight patients underwent 18F-FES PET/CT imaging at baseline, 4-6 weeks during treatment with rintodestrant (interim) and after treatment. After intravenous administration of 200 MBq (+/- 10%) 18F-FES, a 50-min dynamic PET/CT scan of the thorax was performed, followed by a whole body PET/CT scan 60 min post-injection. Blood samples were drawn for measuring whole blood and plasma activity concentration and the parent fraction of 18F-FES. Volumes of interest (VOIs) were placed in the aorta ascendens and in healthy tissues on both dynamic and whole body PET scans. Standard uptake values (SUVs) and target-to-blood ratios (TBR) were calculated. Area under the curves (AUCs) of input functions and time-activity curves were calculated as a measure of uptake in different regions. Results:18F-FES concentration in whole blood (and plasma) significantly (P

Purpose Multiparametric magnetic resonance imaging (mpMRI) is a well-established imaging method for localizing primary prostate cancer (PCa) and for guiding targeted prostate biopsies. [18F]DCFPyL positron emission tomography combined with MRI (PSMA-PET/MRI) might be of additional value to localize primary PCa. The aim of this study was to assess the diagnostic performance of [18F]DCFPyL-PET/MRI vs. mpMRI in tumour localization based on histopathology after robot-assisted radical-prostatectomy (RARP), also assessing biopsy advice for potential image-guided prostate biopsies. Methods Thirty prospectively included patients with intermediate to high-risk PCa underwent [18F]DCFPyL-PET/MRI and mpMRI prior to RARP. Two nuclear medicine physicians and two radiologists assessed tumour localization on [18F]DCFPyL-PET/MRI and on mpMRI respectively, and gave a prostate biopsy advice (2 segments) using a 14-segment model of the prostate. The uro-pathologist evaluated the RARP specimen for clinically significant PCa (csPCa) using the same model. csPCa was defined as any PCa with Grade Group (GG) ≥ 2. The biopsy advice based on imaging was correlated with the final histology in the RARP specimen for a total-agreement analysis. An additional near-agreement correlation was performed to approximate clinical reality. Results Overall, 142 of 420 (33.8%) segments contained csPCa after pathologic examination. The segments recommended for targeted biopsy contained the highest GG PCa segment in 27/30 patients (90.0%) both for [18F]DCFPyL-PET/MRI and mpMRI. Areas under the receiver operating characteristics curves (AUC), sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for the total-agreement detection of csPCa per segment using [18F]DCFPyL-PET/MRI were 0.70, 50.0%, 89.9%, 71.7%, and 77.9%, respectively. These results were 0.75, 54.2%, 94.2%, 82.8%, and 80.1%, respectively, for mpMRI only. Conclusion Both [18F]DCFPyL-PET/MRI and mpMRI were only partly able to detect csPCa on a per-segment basis. An accurate detection (90.0%) of the highest GG lesion at patient-level was observed when comparing both [18F]DCFPyL-PET/MRI and mpMRI biopsy advice with the histopathology in the RARP specimen. So, despite the finding that [18F]DCFPyL-PET/MRI adequately detects csPCa, it does not outperform mpMRI.

Purpose: To investigate whether the dose planned for cardiac structures is associated with the risk of heart disease (HD) in patients with breast cancer treated with radiation therapy, and whether this association is modified by the presence of coronary artery calcification (CAC).Methods and Materials: Radiation therapy planning computed tomographic (CT) scans and corresponding dose distribution maps of 5561 patients were collected, 5300 patients remained after the exclusion of ineligible patients and duplicates; 1899 patients received their CT scan before 2011, allowing long follow-up. CAC was detected automatically. Using an artificial intelligence-based method, the cardiac structures (heart, cardiac chambers, large arteries, 3 main coronary arteries) were segmented. The planned radiation dose to each structure separately and to the whole heart were determined. Patients were assigned to a low-, medium-, or high-dose group based on the dose to the respective heart structure. Information on HD hospitalization and mortality was obtained for each patient. The association of planned radiation dose to cardiac structures with risk of HD was investigated in patients with and without CAC using Cox proportional hazard analysis in the long follow-up population. Tests for interaction were performed.Results: After a median follow-up of 96.0 months (interquartile range, 84.2-110.4 months) in the long follow-up group, 135 patients were hospitalized for HD or died of HD. If the dose to a structure increased 1 Gy, the relative HD risk increased by 3% to 11%. The absolute increase in HD risk was substantially higher in patients with CAC (event-ratelow-dose = 14-15 vs event-ratehigh-dose = 15-34 per 1000 person-years) than in patients without CAC (event-ratelow-dose = 6-8 vs event-ratehigh-dose = 5-17 per 1000 person-years). No interaction between CAC and radiation dose was found.Conclusions: Radiation exposure of cardiac structures is associated with increased risk of HD. Automatic segmentation of cardiac structures enables spatially localized dose estimation, which can aid in the prevention of radiation therapy-induced cardiac damage. This could be especially valuable in patients with breast cancer and CAC.

Summary Background The prognosis of malignant gliomas remains poor. In recurrent disease, chemotherapy can be considered. Patients and methods In this phase II study we determined the anti-tumour efficacy of paclitaxel 200 mg/m2 in a three-hour intravenous infusion every three weeks in chemonaive patients with recurrent high-grade glioma in terms of response, survival, and quality of life. Results In 17 patients (14 glioblastoma multiforme, 3 ana-plastic astrocytoma) 69 paclitaxel cycles were administered. Partial or complete responses were not observed. Stable disease for four to six months was observed in five patients (29%). Median time to progression and median survival were two and 10 months, respectively. Toxicity due to paclitaxel was as to be expected and minor in most cases. Quality of life and mood estimates appeared rather stable over time. Conclusions We conclude that three-weekly 200 mg/m2 paclitaxel chemotherapy for patients with recurrent high-grade gliomas did not lead to major complications or adverse effects on quality of life and mood. However, this therapy is of only very limited value in terms of response and survival in such patients.

Objective To propose EV-derived mRNA as a potential diagnostic biomarker detecting the presence of clear cell renal cell carcinoma (ccRCC). There is currently no kidney cancer specific screening or diagnostic technology. Therefore, one-third of kidney cancer diagnoses occur after the cancer has metastasized and is past curative measures Materials and Methods Urine, plasma, normal tumor adjacent tissue, and tumor tissue was collected from a limited population of ccRCC patients. Extracellular vesicle (EV) isolation was performed on each sample, followed by mRNA extraction from isolated EVs. NanoString® nCounter technology was utilized to count the mRNA transcripts present in matched plasma, urine, tumor tissue, and normal tumor adjacent tissue samples. Results 770 mRNA transcripts related to gene's affecting cancer's progression and metastasis processes were evaluated. Four EV derived mRNA transcripts (ALOX5, RBL2, VEGFA, TLK2) were found specific to urine and cancer tissue samples. Conclusion Four candidate RCC-specific urine EV biomarkers were identified. However, due to the lack of a true negative control and urine collection techniques, further re-examination is necessary for validation. This study demonstrates the promise of defining disease-specific EV biomarkers in liquid biopsy patient samples.

Summary Aims To investigate the prognostic value of baseline imaging features for overall survival (OS) and liver decompensation (LD) in patients with hepatocellular carcinoma (HCC). Design Patients with advanced HCC from the SORAMIC trial were evaluated in this post hoc analysis. Several radiological imaging features were collected from baseline computed tomography (CT) and magnetic resonance imaging (MRI) imaging, besides clinical values. The prognostic value of these features for OS and LD (grade 2 bilirubin increase) was quantified with univariate Cox proportional hazard models and multivariate Least Absolute Shrinkage and Selection Operator (LASSO) regression. Results Three hundred and seventy-six patients were included in this study. The treatment arm was not correlated with OS. LASSO showed satellite lesions, atypical HCC, peritumoral arterial enhancement, larger tumour size, higher albumin–bilirubin (ALBI) score, liver–spleen ratio Conclusions Imaging features showing aggressive tumour biology and poor liver function, in addition to clinical parameters, can serve as imaging biomarkers for OS and LD in patients receiving sorafenib and selective internal radiation therapy for HCC.

ObjectiveRadiofrequency ablation (RFA)±endoscopic resection (ER) is the preferred treatment for early neoplasia in Barrett’s oesophagus (BE). We aimed to report short-term and long-term outcomes for all 1384 patients treated in the Netherlands (NL) from 2008 to 2018, with uniform treatment and follow-up (FU) in a centralised setting.DesignEndoscopic therapy for early BE neoplasia in NL is centralised in nine expert centres with specifically trained endoscopists and pathologists that adhere to a joint protocol. Prospectively collected data are registered in a uniform database. Patients with low/high-grade dysplasia or low-risk cancer, were treated by ER of visible lesions followed by trimonthly RFA sessions of any residual BE until complete eradication of BE (CE-BE). Patients with ER alone were not included.ResultsAfter ER (62% of cases; 43% low-risk cancers) and median 1 circumferential and 2 focal RFA (p25-p75 0–1; 1–2) per patient, CE-BE was achieved in 94% (1270/1348). Adverse events occurred in 21% (268/1386), most commonly oesophageal stenosis (15%), all were managed endoscopically. A total of 1154 patients with CE-BE were analysed for long-term outcomes. During median 43 months (22–69) and 4 endoscopies (1–5), 38 patients developed dysplastic recurrence (3%, annual recurrence risk 1%), all were detected as endoscopically visible abnormalities. Random biopsies from a normal appearing cardia showed intestinal metaplasia (IM) in 14% and neoplasia in 0%. A finding of IM in the cardia was reproduced during further FU in only 33%, none progressed to neoplasia. Frequent FU visits in the first year of FU were not associated with recurrence risk.ConclusionIn a setting of centralised care, RFA±ER is effective for eradication of Barrett’s related neoplasia and has remarkably low rates of dysplastic recurrence. Our data support more lenient FU intervals, with emphasis on careful endoscopic inspection. Random biopsies from neosquamous epithelium and cardia are of questionable value.Netherlands trial register numberNL7039.

Background The introduction of primary HPV screening has doubled the number of colposcopy referrals because of the direct referral of HPV-positive women with a borderline or mild dyskaryosis (BMD) cytology (ASC-US/LSIL) triage test. Further risk-stratification is warranted to improve the efficiency of HPV-based screening. Methods This study evaluated the discriminative power of FAM19A4/miR124-2 methylation, HPV16/18 genotyping and HPV16/18/31/33/45 genotyping in HPV-positive women with BMD (n = 294) in two Dutch screening trials. Absolute CIN3+ risks and colposcopy referrals within one screening round were calculated. Results Methylation analysis discriminated well, yielding a CIN3+ risk of 33.1% after a positive result and a CIN3+ risk of 9.8% after a negative result. HPV16/18 and HPV16/18/31/33/45 genotyping resulted in a 27.6% and 24.6% CIN3+ risk after a positive result, and a 13.2% and 9.1% CIN3+ risk after a negative result. Colposcopy referral percentages were 41.2%, 43.2%, and 66.3% for FAM19A4/miR124-2 methylation, HPV16/18 and HPV16/18/31/33/45 genotyping, respectively. The CIN3+ risk after a negative result could be lowered to 2.8% by combining methylation and extended genotyping, at the expense of a higher referral percentage of 75.5%. Conclusion The use of FAM19A4/miR124-2 methylation and/or HPV genotyping in HPV-positive women with BMD can lead to a substantial reduction in the number of direct colposcopy referrals.

Purpose Accurate prognostic markers are urgently needed to identify diffuse large B-Cell lymphoma (DLBCL) patients at high risk of progression or relapse. Our purpose was to investigate the potential added value of baseline radiomics features to the international prognostic index (IPI) in predicting outcome after first-line treatment. Methods Three hundred seventeen newly diagnosed DLBCL patients were included. Lesions were delineated using a semi-automated segmentation method (standardized uptake value ≥ 4.0), and 490 radiomics features were extracted. We used logistic regression with backward feature selection to predict 2-year time to progression (TTP). The area under the curve (AUC) of the receiver operator characteristic curve was calculated to assess model performance. High-risk groups were defined based on prevalence of events; diagnostic performance was assessed using positive and negative predictive values. Results The IPI model yielded an AUC of 0.68. The optimal radiomics model comprised the natural logarithms of metabolic tumor volume (MTV) and of SUVpeak and the maximal distance between the largest lesion and any other lesion (Dmaxbulk, AUC 0.76). Combining radiomics and clinical features showed that a combination of tumor- (MTV, SUVpeak and Dmaxbulk) and patient-related parameters (WHO performance status and age > 60 years) performed best (AUC 0.79). Adding radiomics features to clinical predictors increased PPV with 15%, with more accurate selection of high-risk patients compared to the IPI model (progression at 2-year TTP, 44% vs 28%, respectively). Conclusion Prediction models using baseline radiomics combined with currently used clinical predictors identify patients at risk of relapse at baseline and significantly improved model performance. Trial registration number and date EudraCT: 2006–005,174-42, 01–08-2008.

Item does not contain fulltext BACKGROUND: The aim of this study was to analyze the stoma-related reinterventions, complications and readmissions after an anterior resection for rectal cancer, based on a cross-sectional nationwide cohort study with 3-year follow-up. METHODS: Rectal cancer patients who underwent a resection with either a functional anastomosis, a defunctioned anastomosis, or Hartmann's procedure (HP) with an end colostomy in 2011 in 71 Dutch hospitals were included. The primary outcome was number of stoma-related reinterventions. RESULTS: Of the 2095 patients with rectal cancer, 1400 patients received an anterior resection and were included in this study; 257 received an initially functional anastomosis, 741 a defunctioned anastomosis, and 402 patients a HP. Of the 1400 included patients, 62% were males, 38% were females and the mean age was 67 years (SD 11.1). Following a primary functional anastomosis, 48 (19%) patients received a secondary stoma. Stoma-related complications occurred in six (2%) patients, requiring reintervention in one (0.4%) case. In the defunctioned anastomosis group, stoma-related complications were present in 92 (12%) patients, and required reintervention in 23 (3%) patients, in 10 (1%) of these more than 1 year after initial resection. Stoma-related complications occurred in 92 (23%) patients after a HP, and required reintervention in 39 (10%) patients in 17 (4%) of cases more than 1 year after initial resection. The permanent stoma rate was 11% and 20%, in the functional anastomosis and the defuctioned anastomosis group, respectively. The end colostomy in the HP group was reversed in 4% of cases. CONCLUSIONS: Construction of a stoma after resection for rectal cancer with preservation of the sphincter is accompanied with long-term stoma-related morbidity. Stoma complications are more frequent after a HP. Even after 1 year, a significant number of reinterventions are required.

Background The aim of this nationwide observational study was to evaluate factors associated with multivisceral resection (MVR), margin status and overall survival in locally advanced colorectal cancer (CRC). Material and methods Patients with (y)pT4, cM0 CRC between 2006 and 2017 were selected from the Netherlands Cancer Registry. Cox-proportional hazards modelling was used for survival analysis, stratified for T4a and T4b. Annual hospital volume cut-off was 75 for colon and 40 for rectal resections. Results A total of 11.930 patients were included and 2410 patients (20.2%) underwent MVR. Factors associated with MVR for colon and rectal cancer besides cT4 category were more recent diagnosis (OR 3.61, CI 95% 3.06–4.25 (colon) and OR 2.72, CI 95% 1.82–4.08 (rectum)) and high hospital volume (OR 1.20, CI 95% 1.05–1.38 (colon) and OR 2.17, CI 95% 1.55–3.04 (rectum)). Patients ≥70 year were less likely to undergo MVR for colon cancer (OR 0.80, 95% CI 0.70–0.90). Risk factors for incomplete resection were cT4 (OR 3.08, CI 95% 2.35–4.04 (colon) and OR 1.82, CI 95% 1.13–2.94 (rectum)) and poor/undifferentiated tumors (OR 1.41, CI 95% 1.14–1.72 (colon) and OR 1.69, CI 95% 1.05–2.74 (rectum)). More recent diagnosis was independently associated with less incomplete resections in colon cancer (OR 0.58, CI 95% 0.40–0.76). Independent predictors of survival were age, resection margin, nodal status and adjuvant chemotherapy, but not MVR. Conclusion Treatment of locally advanced CRC with MVR at population level was influenced by year of diagnosis and hospital volume. Margin status in colon cancer improved substantially over time.

PURPOSE: The sigmoid take-off (STO) was recently introduced as a preferred landmark, agreed upon by expert consensus recommendation, to discern rectal from sigmoid cancer on imaging. Aim of this study was to assess the reproducibility of the STO, explore its potential treatment impact and identify its main interpretation pitfalls.METHODS: Eleven international radiologists (with varying expertise) retrospectively assessed n = 155 patients with previously clinically staged upper rectal/rectosigmoid tumours and re-classified them using the STO as completely below (rectum), straddling the STO (rectosigmoid) or completely above (sigmoid), after which scores were dichotomized as rectum (below/straddling STO) and sigmoid (above STO), being the clinically most relevant distinction. A random subset of n = 48 was assessed likewise by 6 colorectal surgeons. .RESULTS: Interobserver agreement (IOA) for the 3-category score ranged from κ0.19-0.82 (radiologists) and κ0.32-0.72 (surgeons), with highest scores for the most experienced radiologists (κ0.69-0.76). Of the 155 cases, 44 (28%) were re-classified by ≥ 80% of radiologists as sigmoid cancers; 36 of these originally received neoadjuvant treatment which in retrospect might have been omitted if the STO had been applied. Main interpretation pitfalls were related to anatomical variations, borderline cases near the STO and angulation of axial imaging planes.CONCLUSIONS: Good agreement was reached for experienced radiologists. Despite considerable variation among less-expert readers, use of the STO could have changed treatment in ±1/4 of patients in our cohort. Identified interpretation pitfalls may serve as a basis for teaching and to further optimize MR protocols.

Background: Paediatric tumours are often characterised by the presence of recurrent DNA copy number alterations (CNAs). These DNA copy number profiles, obtained from a tissue biopsy, can aid in the correct prognostic classification and therapeutic stratification of several paediatric cancer entities (e.g. MYCN amplification in neuroblastoma) and are part of the routine diagnostic practice. Liquid biopsies (LQBs) offer a potentially safer alternative for such invasive tumour tissue biopsies and can provide deeper insight into tumour heterogeneity. Procedure: The robustness and reliability of LQB CNA analyses was evaluated. We performed retrospective CNA profiling using shallow whole-genome sequencing (sWGS) on paired plasma circulating cell-free DNA (cfDNA) and tissue DNA samples from routinely collected samples from paediatric patients (n = 128) representing different tumour entities, including osteosarcoma, Ewing sarcoma, rhabdomyosarcoma, Wilms tumour, brain tumours and neuroblastoma. Results: Overall, we observed a good concordance between CNAs in tissue DNA and cfDNA. The main cause of CNA discordance was found to be low cfDNA sample quality (i.e. the ratio of cfDNA (700 bp)). Furthermore, CNAs were observed that were present in cfDNA and not in tissue DNA, or vice-versa. In neuroblastoma samples, no false-positives or false-negatives were identified for the detection of the prognostic marker MYCN amplification. Conclusion: In future prospective studies, CNA analysis on LQBs that are of sufficient quality can serve as a complementary assay for CNA analysis on tissue biopsies, as either cfDNA or tissue DNA can contain CNAs that cannot be identified in the other biomaterial.

Many countries had to suspend their colorectal cancer (CRC) screening pro-gramme as a result of the COVID-19 pandemic. This eventually may lead to postponed diag-noses of premalignant lesions and CRC, resulting in increased incidence or more advanced CRCs rates. This study aimed to assess the impact of the COVID-19 pandemic on incidence and stage distribution of CRCs in the Netherlands, by monitoring CRC diagnoses and stage distribution in the months before, during and after the first COVID-19 wave. Data on inci-dence and stage distribution of CRCs of individuals aged 55-75 years in 25 hospitals in the Netherlands were extracted from the Netherlands Cancer Registry. The observed incidence after the suspension (March 2020-December 2020) was compared to the expected incidence in the same period. In the period April to June 2020, we observed the largest decrease in the total incidence of CRC. We found that 48% of the decrease was due to stage I, 23% due to stage II, 23% due to stage III and 5% due to stage IV. After gradually resuming screening mid May 2020, we observed an increase in CRC diagnoses from July 2020 onwards. As of October 2020, the observed number of diagnoses was higher than the expected number. As the decrease was mainly limited to stage I CRCs, it seems that the temporary suspension of the CRC screening programme due to the COVID-19 pandemic will have a minimal long-term impact on stage distribution and CRC mortality. 2021 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Background: Non–muscle-invasive bladder cancer (NMIBC) is characterized by frequent recurrence of the disease, which is difficult to predict. Objective: To combine digital histopathology slides with clinical data to predict 1- and 5-yr recurrence-free survival of NMIBC patients using deep learning. Design, setting, and participants: Data of patients undergoing a transurethral resection of a bladder tumor between 2000 and 2018 at a Dutch academic medical center were selected. Corresponding histological slides were digitized. A three-step approach was used to predict 1- and 5-yr recurrence-free survival. First, a segmentation network was used to detect the urothelium on the digital histopathology slides. Second, a selection network was trained for the selection of patches associated with recurrence. Third, a classification network, combining the information of the selection network with clinical data, was trained to give the probability of 1- and 5-yr recurrence-free survival. Outcome measurements and statistical analysis: The accuracy of the deep learning–based model was compared with a multivariable logistic regression model using clinical data only. Results and limitations: In the 1- and 5-yr follow-up cohorts, 359 and 281 patients were included with recurrence rates of 27% and 63%, respectively. The areas under the curve (AUCs) of the model combining digital histopathology slide data with clinical data were 0.62 and 0.76 for 1- and 5-yr recurrence predictions, respectively, which were higher than those of the model using digital histopathology slide data only (AUCs of 0.56 and 0.72, respectively) and the multivariable logistic regression (AUCs of 0.58 and 0.57, respectively). Conclusions: In our population, the deep learning–based model combining digital histopathology slides and clinical data enhances the prediction of recurrence (within 5 yr) compared with models using clinical data or image data only. Patient summary: By combining histopathology images and patient record data using deep learning, the prediction of recurrence in bladder cancer patients is enhanced. The proposed deep learning method showed promising results for the 5-yr prediction of recurrence when combining clinical data and digital histopathology images. Although not yet validated for clinical practice, this deep learning approach has the potential to improve recurrence prediction.

Contains fulltext : 249895.pdf (Publisher’s version ) (Open Access) AIM: The aim of this study was to evaluate interobserver variability between individual pathologists and a panel of pathologists in the histopathological assessment of advanced colorectal neoplasms in the Dutch bowel cancer screening population. METHODS AND RESULTS: Histological slides of adenomas with high-grade dysplasia and early colorectal carcinomas (CRC) from 20 different laboratories were reviewed by the pathology panel of the Dutch bowel screening programme. Interobserver variability was reported by descriptive statistics. In addition, potential clinical consequences of discrepancies were evaluated. A total of 104 cases of adenomas with high-grade dysplasia and 83 early CRCs were reviewed. Discrepancies were observed in 41 of 104 (39.4%) adenoma cases, which potentially had clinical consequences in 16 (15.4%) cases. For CRC, discrepancies were shown in 44 of 83 cases (53.0%) and would have potentially led to alternative treatment strategies in 25 (30.1%) cases. Most frequently, discrepancies were observed in the assessment of lymphovascular invasion (23 of 73 cases, 31.5%). CONCLUSION: This study showed that considerable interobserver variability is present in the histopathological assessment of advanced colorectal neoplasia, which may impact upon treatment choices. Additional stains and education, as well as intercollegial consultation, might decrease this variability.

Background Transperineal magnetic resonance imaging–transrectal ultrasound fusion guided biopsy (MFGB) is an increasingly popular technique due to increasing rates of biopsy-related infections. However, its widespread implementation has been hampered by the supposed necessity of epidural or general anesthesia. Objective To demonstrate the technique, feasibility, and results of transperineal MFGB under local anesthesia, in an ambulatory setting without the administration of prophylactic antibiotics. Design, setting, and participants This single-center study enrolled consecutive biopsy-naive men with a clinical suspicion of prostate cancer into a prospective database between November 2015 and November 2020. Men with Prostate Imaging Reporting and Data System (PI-RADS) version 2 scores 3–5 underwent transperineal MFGB. Surgical procedure Transperineal MFGB was performed in an ambulatory setting under local anesthesia by a single operator. Measurements Procedure-associated adverse events were recorded. Patient discomfort during both the local anesthesia and the biopsy procedure was determined using a visual analogic scale (0–10). Detection rates of grade group (GG) ≥2 prostate cancer and the proportion of men with GG 1 cancer were assessed. Results and limitations A total of 1097 eligible men underwent transperineal MFGB. The complication rate was 0.73% (8/1097); complications comprised five (0.46%) urinary tract infections including one hospitalization and three (0.27%) urinary retentions. In 735 men, the median pain scores were 2 (interquartile range [IQR] 2–3) for the local anesthesia procedure and 1 (IQR 0-2) for the biopsy. Prostate cancer was detected in 84% (926/1097) of men; 66% (723/1097) had GG ≥2 and 19% (203/1097) GG 1. Conclusions Transperineal MFGB can safely be performed as an outpatient procedure under local anesthesia in an ambulatory setting. The detection rate of clinically significant prostate cancer is high, and biopsy is well tolerated. Although no antibiotic prophylaxis was used, the rate of infectious complications is practicably negligible. Patient summary This article shows how tissue samples (biopsies) can accurately be obtained from suspicious regions seen on prostate magnetic resonance imaging via needles inserted in the perineum (skin between the scrotum and the anus) in men with suspected prostate cancer. This technique appears to be very well tolerated under local anesthesia and has a lower risk of infection without antibiotic prophylaxis than the more common biopsy route through the rectum, with antibiotics.

Background and purpose: Accelerated partial breast irradiation (APBI) may benefit from the MR-Linac for target definition, patient setup, and motion monitoring. In this planning study, we investigated whether prone or supine position is dosimetrically beneficial for APBI on an MR-Linac and we evaluated patient comfort. Materials and methods: Twenty-patients (9 postoperative, 11 preoperative) with a DCIS or breast tumor

The aim of this study was to evaluate the in vivo performance of a prototype dual-crystal [lutetium oxyorthosilicate (LSO)/sodium iodide (NaI)] dual-head coincidence camera (DHC) for PET and SPET (LSO-PS), in comparison to BGO-PET with fluorine-18 fluorodeoxyglucose (FDG) in oncology. This follows earlier reports that LSO-PS has noise-equivalent counting (NEC) rates comparable to partial ring BGO-PET, i.e. clearly higher than standard NaI DHCs. Twenty-four randomly selected oncological patients referred for whole-body FDG-PET underwent BGO-PET followed by LSO-PS. Four nuclear medicine physicians were randomised to read a single scan modality, in terms of lesion intensity, location and likelihood of malignancy. BGO-PET was considered the gold standard. Forty-eight lesions were classified as positive with BGO-PET, of which LSO-PS identified 73% (95% CI 60-86%). There was good observer agreement for both modalities in terms of intensity, location and interpretation. Lesions were missed by LSO-PS in 13 patients in the chest (n=6), neck (n=3) and abdomen (n=4). The diameter of these lesions was estimated to be 0.5-1 cm. Initial results justify further evaluation of LSO-PS in specific clinical situations, especially if a role as an instrument of triage for PET is foreseen.

Somatic copy number alterations can be detected in cell-free DNA (cfDNA) by shallow whole genome sequencing (sWGS). PCR is typically included in library preparations, but a PCR-free method could serve as a high-throughput alternative. To evaluate a PCR-free method for research and diagnostics, archival peripheral blood or bone marrow plasma samples, collected in EDTA- or lithium-heparin–containing tubes, were collected from patients with non–small-cell lung cancer (n = 10 longitudinal samples; 4 patients), B-cell lymphoma (n = 31), and acute myeloid leukemia (n = 15), or from healthy donors (n = 14). sWGS was performed on PCR-free and PCR library preparations, and the mapping quality, percentage of unique reads, genome coverage, fragment lengths, and copy number profiles were compared. The percentage of unique reads was significantly higher for PCR-free method compared with PCR method, independent of the type of collection tube: EDTA PCR-free method, 96.4% (n = 35); EDTA PCR method, 85.1% (n = 32); heparin PCR-free method, 94.5% (n = 25); and heparin PCR method, 89.4% (n = 10). All other evaluated metrics were highly comparable for PCR-free and PCR library preparations. These results demonstrate the feasibility of somatic copy number alteration detection by PCR-free sWGS using cfDNA from plasma collected in EDTA- or lithium-heparin–containing tubes and pave the way for an automated cfDNA analysis workflow for samples from cancer patients.

Background and purpose Positional verification during single fraction lung SBRT could increase confidence and reduce the chance of geographic miss. As planar 2DkV imaging during VMAT irradiation is already available on current linear accelerators, markerless tracking based on these images could offer widely available and low-cost verification. We evaluated treatment delivery data and template matching and triangulation for 3D-positional verification during free-breathing, single fraction (34 Gy), 10 MV flattening-filter-free VMAT lung SBRT. Methods and materials Tumor tracking based on kV imaging at 7 frames/second was performed during irradiation in 6 consecutive patients (7 lesions). Tumor characteristics, tracking ability, comparison of tracking displacements with CBCT-based shifts, tumor position relative to the PTV margin, and treatment times are reported. Results For all 7 lesions combined, 3D tumor position could be determined for, on average, 71% (51–84%) of the total irradiation time. Visually estimated tracked and automated match +/− manually-corrected CBCT-derived displacements generally agreed within 1 mm. During the tracked period, the longitudinal, lateral and vertical position of the tumor was within a 5 mm/3 mm PTV margin 95.5/85.3% of the time. The PTV was derived from the ITV including all tumor motion. The total time from first set-up imaging to end of the last arc was 18.3–31.4 min (mean = 23.4, SD = 4.1). Conclusion 3D positional verification during irradiation of small lung targets with limited motion, was feasible. However, tumor position could not be determined for on average 29% of the time. Improvements are needed. Margin reduction may be feasible. Imaging and delivery of a single 34 Gy fraction was fast.

Ependymomas encompass a heterogeneous group of central nervous system (CNS) neoplasms that occur along the entire neuroaxis. In recent years, extensive (epi-)genomic profiling efforts have identified several molecular groups of ependymoma that are characterized by distinct molecular alterations and/or patterns. Based on unsupervised visualization of a large cohort of genome-wide DNA methylation data, we identified a highly distinct group of pediatric-type tumors (n = 40) forming a cluster separate from all established CNS tumor types, of which a high proportion were histopathologically diagnosed as ependymoma. RNA sequencing revealed recurrent fusions involving the pleomorphic adenoma gene-like 1 (PLAGL1) gene in 19 of 20 of the samples analyzed, with the most common fusion being EWSR1:PLAGL1 (n = 13). Five tumors showed a PLAGL1:FOXO1 fusion and one a PLAGL1:EP300 fusion. High transcript levels of PLAGL1 were noted in these tumors, with concurrent overexpression of the imprinted genes H19 and IGF2, which are regulated by PLAGL1. Histopathological review of cases with sufficient material (n = 16) demonstrated a broad morphological spectrum of tumors with predominant ependymoma-like features. Immunohistochemically, tumors were GFAP positive and OLIG2- and SOX10 negative. In 3/16 of the cases, a dot-like positivity for EMA was detected. All tumors in our series were located in the supratentorial compartment. Median age of the patients at the time of diagnosis was 6.2 years. Median progression-free survival was 35 months (for 11 patients with data available). In summary, our findings suggest the existence of a novel group of supratentorial neuroepithelial tumors that are characterized by recurrent PLAGL1 fusions and enriched for pediatric patients.

Biochemical recurrence of prostate cancer (PCa) after curative radiotherapy is defined as a prostate-specific antigen (PSA) rise of ≥2 ng/ml above the nadir ("Phoenix criteria", 2005). With the introduction of prostate-specific membrane antigen positron emission tomography (PSMA-PET), the ability to localise PCa recurrences has increased markedly. Here, we reviewed 315 patients scanned with PSMA-PET after curative radiotherapy in the Prostate Cancer Network Amsterdam (2015-2018). Sixty-three patients (20.3%) were scanned below the Phoenix threshold (PSA rise

OBJECTIVE: Adult granulosa cell tumors (aGCTs) represent a rare, hormonally active subtype of ovarian cancer that has a tendency to relapse late and repeatedly. Current serum hormone markers are inaccurate in reflecting tumor burden in a subset of aGCT patients, indicating the need for a novel biomarker. We investigated the presence of circulating tumor DNA (ctDNA) harboring a FOXL2 or TERT promoter mutation in serial plasma samples of aGCT patients to determine its clinical value for monitoring disease.METHODS: In a national multicenter study, plasma samples (n = 110) were prospectively collected from 21 patients with primary (n = 3) or recurrent (n = 18) aGCT harboring a FOXL2 402C > G and/or TERT (C228T or C250T) promoter mutation. Circulating cell-free DNA was extracted and assessed for ctDNA containing one of either mutations using droplet digital PCR (ddPCR). Fractional abundance of FOXL2 mutant and TERT mutant ctDNA was correlated with clinical parameters.RESULTS: FOXL2 mutant ctDNA was found in plasma of 11 out of 14 patients (78.6%) with aGCT with a confirmed FOXL2 mutation. TERT C228T or TERT C250T mutant ctDNA was detected in plasma of 4 of 10 (40%) and 1 of 2 patients, respectively. Both FOXL2 mutant ctDNA and TERT promoter mutant ctDNA levels correlated with disease progression and treatment response in the majority of patients.CONCLUSIONS: FOXL2 mutant ctDNA was present in the majority of aGCT patients and TERT promoter mutant ctDNA has been identified in a smaller subset of patients. Both FOXL2 and TERT mutant ctDNA detection may have clinical value in disease monitoring.

Background: Despite the low recurrence rate of resected nonfunctional pancreatic neuroendocrine tumors (NF-pNETs), nearly all patients undergo long-term surveillance. A prediction model for recurrence may help select patients for less intensive surveillance or identify patients for adjuvant therapy. The objective of this study was to assess the external validity of a recently published model predicting recurrence within 5 years after surgery for NF-pNET in an international cohort. This prediction model includes tumor grade, lymph node status and perineural invasion as predictors. Methods: Retrospectively, data were collected from 7 international referral centers on patients who underwent resection for a grade 1–2 NF-pNET between 1992 and 2018. Model performance was evaluated by calibration statistics, Harrel’s C-statistic, and area under the curve (AUC) of the receiver operating characteristic curve for 5-year recurrence-free survival (RFS). A sub-analysis was performed in pNETs >2 cm. The model was improved to stratify patients into 3 risk groups (low, medium, high) for recurrence. Results: Overall, 342 patients were included in the validation cohort with a 5-year RFS of 83% (95% confidence interval [CI]: 78–88%). Fifty-eight patients (17%) developed a recurrence. Calibration showed an intercept of 0 and a slope of 0.74. The C-statistic was 0.77 (95% CI: 0.70–0.83), and the AUC for the prediction of 5-year RFS was 0.74. The prediction model had a better performance in tumors >2 cm (C-statistic 0.80). Conclusions: External validity of this prediction model for recurrence after curative surgery for grade 1–2 NF-pNET showed accurate overall performance using 3 easily accessible parameters. This model is available via www.pancreascalculator.com.

Pancreatic cancer (PC) survival is poor, as detection usually occurs late, when treatment options are limited. Screening of high‐risk individuals may enable early detection and a more favorable prognosis. Knowledge gaps prohibit establishing the effectiveness of screening. We developed a Microsimulation Screening Analysis model to analyze the impact of relevant uncertainties on the effect of PC screening in high‐risk individuals. The model simulates two base cases: one in which lesions always progress to PC and one in which indolent and faster progressive lesions coexist. For each base case, the effect of annual and 5‐yearly screening with endoscopic ultrasonography/magnetic resonance imaging was evaluated. The impact of variance in PC risk, screening test characteristics and surgery‐related mortality was evaluated using sensitivity analyses. Screening resulted in a reduction of PC mortality by at least 16% in all simulated scenarios. This reduction depended strongly on the natural disease course (annual screening: −57% for “Progressive‐only” vs −41% for “Indolent Included”). The number of screen and surveillance tests needed to prevent one cancer death was impacted most by PC risk. A 10% increase in test sensitivity reduced mortality by 1.9% at most. Test specificity is important for the number of surveillance tests. In conclusion, screening reduces PC mortality in all modeled scenarios. The natural disease course and PC risk strongly determines the effectiveness of screening. Test sensitivity seems of lesser influence than specificity. Future research should gain more insight in PC pathobiology to establish the true value of PC screening in high‐risk individuals., What's new? About 10 percent of pancreatic cancers occur in individuals with inherited risk factors. While screening such high‐risk individuals can facilitate the detection of precursor lesions and early‐stage cancer, the extent to which benefits outweigh harms, including overdiagnosis, remains unknown. Here, using a microsimulation model, the authors explored uncertainties concerning the early detection of pancreatic cancer and analyzed the impact of these uncertainties on the effect of screening. In all simulated scenarios, screening was associated with reduced pancreatic cancer mortality. The effectiveness of screening was most strongly impacted by characteristics of natural disease course and level of pancreatic cancer risk

Contains fulltext : 235724.pdf (Publisher’s version ) (Open Access) BACKGROUND & AIMS: Many countries have introduced colorectal cancer (CRC) screening programs with fecal immunochemical tests (FITs), and follow-up colonoscopies for individuals with a positive FIT result. In order to make an informed decision to participate, individuals must be informed about the benefits and harms of FIT-based screening and subsequent colonoscopy. Colonoscopy-related fatal complications in FIT-based screening are understudied. We aimed to estimate the colonoscopy-related mortality in a national FIT-based CRC screening program. METHODS: Colonoscopy-related mortality within 30 days after colonoscopy was assessed by analysis of data from national endoscopy complication databases in the Netherlands, determining the excess 30-day rate of death in FIT-positive individuals undergoing colonoscopy vs FIT-negative individuals (based on data from the national screening database), and determining the rate of likely colonoscopy-related deaths based on registered causes of death by the Statistics Netherlands. RESULTS: Between October 2013 and December 2017, 172,797 participants underwent colonoscopy after a positive result from a FIT in the Dutch national CRC screening program; 13,848 participants received a diagnosis of CRC. The reported fatal complication rate was 0.23 per 10,000 FIT-positive participants (or 1 per 43,199; 95% CI, 0.090 - 0.60) undergoing colonoscopy, whereas this was 0.91 per 10,000 FIT-positive participants (or 1 per 10,961; 95% CI, 0.44 - 1.38) according to the excess death rate. Likely colonoscopy-related causes of death were reported in 0.86 per 10,000 FIT-positive participants (or 1 per 11,236; 95% CI, 0.48 - 1.63) who underwent colonoscopy, of which 50% considered cardiovascular events. CONCLUSIONS: Colonoscopy-related mortality within the Dutch FIT-based CRC screening program was estimated to range from 0.23 to 0.91 per 10,000 FIT-positive participants undergoing colonoscopy. These findings indicate underreporting of fatal complications in registries and a noteworthy incidence of fatal cardiovascular adverse events that requires further investigation. Nevertheless, the harm of FIT-based CRC screening is vastly outweighed by the benefits.

Background Online adaptive radiotherapy has the potential to reduce toxicity for patients treated for rectal cancer because smaller planning target volumes (PTV) margins around the entire clinical target volume (CTV) are required. The aim of this study is to describe the first clinical experience of a Conebeam CT (CBCT)-based online adaptive workflow for rectal cancer, evaluating timing of different steps in the workflow, plan quality, target coverage and patient compliance. Methods Twelve consecutive patients eligible for 5 × 5 Gy pre-operative radiotherapy were treated on a ring-based linear accelerator with a multidisciplinary team present at the treatment machine for each fraction. The accelerator is operated using an integrated software platform for both treatment planning and delivery. In all directions for all CTVs a PTV margin of 5 mm was used, except for the cranial/caudal borders of the total CTV where a margin of 8 mm was applied. A reference plan was generated based on a single planning CT. After aligning the patient the online adaptive procedure started with acquisition of a CBCT. The planning CT scan was registered to the CBCT using deformable registration and a synthetic CT scan was generated. With the support of artificial intelligence, structure guided deformation and the synthetic CT scan contours were adapted by the system to match the anatomy on the CBCT. If necessary, these contours were adjusted before a new plan was generated. A second and third CBCT were acquired to validate the new plan with respect to CTV coverage just before and after treatment delivery, respectively. Treatment was delivered using volumetric modulated arc treatment (VMAT). All steps in this process were defined and timed. Results On average the timeslot needed at the treatment machine was 34 min. The process of acquiring a CBCT, evaluating and adjusting the contours, creating the new plan and verifying the CTV on the CBCT scan took on average 20 min. Including delivery and post treatment verification this was 26 min. Manual adjustments of the target volumes were necessary in 50% of fractions. Plan quality, target coverage and patient compliance were excellent. Conclusions First clinical experience with CBCT-based online adaptive radiotherapy shows it is feasible for rectal cancer. Trial registration Medical Research Involving Human Subjects Act (WMO) does not apply to this study and was retrospectively approved by the Medical Ethics review Committee of the Academic Medical Center (W21_087 # 21.097; Amsterdam University Medical Centers, Location Academic Medical Center, Amsterdam, The Netherlands).

PURPOSE: We sought to identify a subset of patients in whom an extended pelvic lymph node dissection during robot-assisted laparoscopic radical prostatectomy for localized prostate cancer could be omitted when preoperative prostate specific membrane antigen positron emission tomography showed no lymph node metastatic prostate cancer. MATERIALS AND METHODS: A total of 434 patients who underwent prostate specific membrane antigen positron emission tomography prior to robot-assisted laparoscopic radical prostatectomy and extended pelvic lymph node dissection were retrospectively analyzed. Patients were excluded from analysis when the prostate specific membrane antigen positron emission tomography showed evidence of distant metastases. The primary outcome was whether a negative for metastases prostate specific membrane antigen positron emission tomography was able to correctly rule out pelvic lymp node metastases after extended pelvic lymph node dissection, ie its negative predictive value. RESULTS: Overall sensitivity, specificity, positive predictive value and negative predictive value of prostate specific membrane antigen positron emission tomography for the detection of pelvic lymp node metastases were 37.9%, 94.1%, 64.3% and 84.4%, respectively. The negative predictive value of prostate specific membrane antigen positron emission tomography in patients with intermediate risk prostate cancer was 91.6% (95% CI 86-97), compared to 81.4% (95% CI 77-86) in patients with high risk prostate cancer. When only assessing patients with

Background: The treatment of locally advanced or recurrent anorectal cancer requires radical surgery such as extralevator abdominoperineal resection and pelvic exenteration. Larger defects require flap reconstruction. The authors evaluated outcomes of different perineal reconstruction techniques. Methods: A systematic search was performed in the PubMed, Embase, and Cochrane databases. Studies reporting outcomes on perineal flap reconstruction in patients with anal or colorectal cancer were included. Data on patient characteristics, surgical details, perineal and donor-site complications, revision surgery, mortality, and quality of life were extracted. Articles were assessed using the Group Reading Assessment and Diagnostic Evaluation approach. Results: The authors included 58 mainly observational studies comprising 1988 patients. Seventy-three percent of patients had rectal cancer. The majority of 910 abdominoperineal resection patients underwent reconstruction with rectus abdominis flaps (91 percent). Dehiscence (15 to 32 percent) and wound infection (8 to 16 percent) were the most common complications. Partial flap necrosis occurred in 2 to 4 percent and flap loss occurred in 0 to 2 percent. Perineal herniation was seen in 6 percent after gluteal flap reconstruction and in 0 to 1 percent after other types of reconstruction. Donor-site complications were substantial but were reported inconsistently. Conclusions: Clinical outcome data on perineal reconstruction after exenterative surgery are mostly of very low quality. Perineal reconstruction after pelvic exenteration is complex and requires a patient-tailored approach. Primary defect size, reconstruction aims, donor-site availability, and long-term morbidity should be taken into account. This review describes the clinical outcomes of four flap reconstruction techniques. Shared clinical decision-making on perineal reconstruction should be based on these present comprehensive data.

Summary Background: Fluorescence angiography (FA) assesses anastomotic perfusion during esophagectomy with gastric conduit reconstruction, but its interpretation is subjective. This study evaluated time to fluorescent enhancement in the gastric conduit, with the aim to determine a threshold to predict postoperative anastomotic complications. Methods: In a prospective cohort study, all consecutive patients undergoing esophagectomy with gastric conduit reconstruction from July 2018 to October 2019 were included. FA was performed before anastomotic reconstruction following injection of indocyanine green (ICG). During FA, the following time points were recorded: ICG injection, first fluorescent enhancement in the lung, at the base of the gastric conduit, at the planned anastomotic site, and at ICG watershed or in the tip of the gastric conduit. Anastomotic complications including anastomotic leakage and clinically relevant strictures were documented. Results: Eighty-four patients were included, the majority (67 out of 84, 80%) of which underwent an Ivor Lewis procedure. After a median follow-up of 297 days, anastomotic leakage was observed in 12 out of 84 (14.3%) and anastomotic stricture in 12 out of 82 (14.6%). Time between ICG injection and enhancement in the tip was predictive for anastomotic leakage (P = 0.174, area under the curve = 0.731), and a cut-off value of 98 seconds was derived (specificity: 98%). All times to enhancement at the planned anastomotic site and ICG watershed were significantly predictive for the occurrence of a stricture, however area under the curves were Conclusions: The identified fluorescent threshold can be used for intraoperative decision making or to identify potentially high-risk patients for anastomotic leakage after esophagectomy with gastric conduit reconstruction.

Purpose Metabolically active tumour volume (MATV) is a potential quantitative positron emission tomography (PET) imaging biomarker in melanoma. Accumulating data indicate that low MATV may predict increased chance of response to immunotherapy and overall survival. However, metastatic melanoma can present with numerous (small) tumour lesions, making manual tumour segmentation time-consuming. The aim of this study was to evaluate multiple semi-automatic segmentation workflows to determine reliability and reproducibility of MATV measurements in patients with metastatic melanoma. Methods An existing cohort of 64 adult patients with histologically proven metastatic melanoma was used in this study. 18F-FDG PET/CT diagnostic baseline images were acquired using a European Association of Nuclear Medicine (EANM) Research Limited–accredited Siemens Biograph mCT PET/CT system (Siemens Healthineers, Knoxville, USA). PET data were analysed using manual, gradient-based segmentation and five different semi-automatic methods: three direct PET image–derived delineations (41MAX, A50P and SUV40) and two based on a majority-vote approach (MV2 and MV3), without and with (suffix ‘+’) manual lesion addition. Correlation between the different segmentation methods and their respective associations with overall survival was assessed. Results Correlation between the MATVs derived by the manual segmentation and semi-automated tumour segmentations ranged from R2 = 0.41 for A50P to R2 = 0.85 for SUV40+ and MV2+, respectively. Manual MATV segmentation did not differ significantly from the semi-automatic methods SUV40 (∆MATV mean ± SD 0.08 ± 0.60 mL, P = 0.303), SUV40+ (∆MATV − 0.10 ± 0.51 mL, P = 0.126), MV2+ (∆MATV − 0.09 ± 0.62 mL, P = 0.252) and MV3+ (∆MATV − 0.03 ± 0.55 mL, P = 0.615). Log-rank tests showed statistically significant overall survival differences between above and below median MATV patients for all segmentation methods with areas under the ROC curves of 0.806 for manual segmentation and between 0.756 [41MAX] and 0.807 [MV3+] for semi-automatic segmentations. Conclusions Simple and fast semi-automated FDG PET segmentation workflows yield accurate and reproducible MATV measurements that correlate well with manual segmentation in metastatic melanoma. The most readily applicable and user-friendly SUV40 method allows feasible MATV measurement in prospective multicentre studies required for validation of this potential PET imaging biomarker for clinical use.

The diagnostic work‐up of patients suspected for myelodysplastic syndromes is challenging and mainly relies on bone marrow morphology and cytogenetics. In this study, we developed and prospectively validated a fully computational tool for flow cytometry diagnostics in suspected‐MDS. The computational diagnostic workflow consists of methods for pre‐processing flow cytometry data, followed by a cell population detection method (FlowSOM) and a machine learning classifier (Random Forest). Based on a six tubes FC panel, the workflow obtained a 90% sensitivity and 93% specificity in an independent validation cohort. For practical advantages (e.g., reduced processing time and costs), a second computational diagnostic workflow was trained, solely based on the best performing single tube of the training cohort. This workflow obtained 97% sensitivity and 95% specificity in the prospective validation cohort. Both workflows outperformed the conventional, expert analyzed flow cytometry scores for diagnosis with respect to accuracy, objectivity and time investment (less than 2 min per patient).

Purpose: To understand the role of routine follow-up visits in addressing prostate cancer survivors’ supportive care and information needs. Methods: We audio-recorded follow-up visits of 32 prostate cancer survivors. Follow-up visits were analyzed according to the Verona Network of Sequence Analysis. We categorized survivors’ cues, concerns, and questions into five supportive care domains and divided the responses by the healthcare professionals into providing versus reducing space that is to determine whether or not the response invites the patient to talk more about the expressed cue or concern. Results: Prostate cancer survivors mostly expressed cues, concerns, and questions (in the health system and information domain) about test results, potential impotence treatment, follow-up appointments, and (their) cancer treatment during follow-up visits. Survivors also expressed urinary complaints (physical and daily living domain) and worry about the recurrence of prostate cancer (psychological domain). Healthcare professionals were two times more likely to provide space on cues and concerns related to the physical and daily living domain than to psychological related issues. Conclusion: Follow-up visits can serve to address prostate cancer survivors’ supportive care and information needs, especially on the health system, information, and physical and daily living domain. Survivors also expressed problems in the psychological domain, although healthcare professionals scarcely provided space to these issues. We would like to encourage clinicians to use these results to personalize follow-up care. Also, these data can be used to develop tailored (eHealth) interventions to address supportive care and information needs and to develop new models of survivorship care delivery.

Background Although we previously proposed a nomogram to predict malignancy in intraductal papillary mucinous neoplasms (IPMN) and validated it in an external cohort, its application is challenging without data on tumor markers. Moreover, existing nomograms have not been compared. This study aimed to develop a nomogram based on radiologic findings and to compare its performance with previously proposed American and Korean/Japanese nomograms. Methods We recruited 3708 patients who underwent surgical resection at 31 tertiary institutions in eight countries, and patients with main pancreatic duct > 10 mm were excluded. To construct the nomogram, 2606 patients were randomly allocated 1:1 into training and internal validation sets, and area under the receiver operating characteristics curve (AUC) was calculated using 10-fold cross validation by exhaustive search. This nomogram was then validated and compared to the American and Korean/Japanese nomograms using 1102 patients. Results Among the 2606 patients, 90 had main-duct type, 900 had branch-duct type, and 1616 had mixed-type IPMN. Pathologic results revealed 1628 low-grade dysplasia, 476 high-grade dysplasia, and 502 invasive carcinoma. Location, cyst size, duct dilatation, and mural nodule were selected to construct the nomogram. AUC of this nomogram was higher than the American nomogram (0.691 vs. 0.664, p = 0.014) and comparable with the Korean/Japanese nomogram (0.659 vs 0.653, p = 0.255). Conclusions A novel nomogram based on radiologic findings of IPMN is competitive for predicting risk of malignancy. This nomogram would be clinically helpful in circumstances where tumor markers are not available. The nomogram is freely available at http://statgen.snu.ac.kr/software/nomogramIPMN.

ObjectiveWe aimed to determine the long-term yield of pancreatic cancer surveillance in hereditary predisposed high-risk individuals.DesignFrom 2006 to 2019, we prospectively enrolled asymptomatic individuals with an estimated 10% or greater lifetime risk of pancreatic ductal adenocarcinoma (PDAC) after obligatory evaluation by a clinical geneticist and genetic testing, and subjected them to annual surveillance with both endoscopic ultrasonography (EUS) and MRI/cholangiopancreatography (MRI/MRCP) at each visit.Results366 individuals (201 mutation-negative familial pancreatic cancer (FPC) kindreds and 165 PDAC susceptibility gene mutation carriers; mean age 54 years, SD 9.9) were followed for 63 months on average (SD 43.2). Ten individuals developed PDAC, of which four presented with a symptomatic interval carcinoma and six underwent resection. The cumulative PDAC incidence was 9.3% in the mutation carriers and 0% in the FPC kindreds (pConclusionThe diagnostic yield of PDAC was substantial in established high-risk mutation carriers, but non-existent in the mutation-negative proven FPC kindreds. Nevertheless, timely identification of resectable lesions proved challenging despite the concurrent use of two imaging modalities, with EUS outperforming MRI/MRCP. Overall, surveillance by imaging yields suboptimal results with a clear need for more sensitive diagnostic markers, including biomarkers.

Purpose The aim of the present study is to investigate the prevalence of body image distress among head and neck cancer (HNC) patients after treatment and to examine its association with sociodemographic and clinical factors, health-related quality of life (HRQOL), HNC symptoms, sexuality, self-compassion, and psychological distress. Second, we aim to explore daily life experiences of HNC patients regarding body image. Methods A cross-sectional survey among HNC patients investigated the prevalence of body image distress based on the Body Image Scale. Multivariable logistic regression analysis was applied to study associations with sociodemographic and clinical factors, HRQOL (EORTC QLQ-C30), HNC symptoms (QLQ-HN43), sexuality (FSFI-6; IIEF-5), self-compassion (SCS-SF), and psychological distress (HADS). Qualitative data from a body image writing intervention was used to explore experiences in daily life related to body image. Results Body image distress was prevalent in 13–20% (depending on cut-off scores) of 233 HNC patients. Symptoms of depression (p p p = 0.001), problems with wound healing (p = 0.013), and larger extent of surgery (p = 0.014) were associated with having body image distress. This model explained 67% of variance. Writing interventions of 40 HNC patients showed that negative body image experiences were related to appearance and function, with social functioning problems described most often. Conclusion Prevalence of body image distress in HNC patients, using different cut-off scores, is 13–20%. Younger patients, patients after extensive surgery, and patients who had wound healing problems are most at risk. There is a significant association between body image distress and depressive symptoms and social functioning.

Two nomograms have been developed to predict the outcome of positron emission tomography (PET)/computed tomography (CT) imaging with68Ga-labeled ligands for prostate-specific membrane antigen (68Ga-PSMA) for patients with rising prostate-specific antigen after radical prostatectomy (RP). These nomograms quantify the ability of PSMA PET/CT to detect prostate cancer recurrences, and therefore provide critical information in determining the optimal timing for PSMA PET/CT in guiding salvage therapies. We validated the ability of these nomograms to accurately predict PET/CT outcome using another ligand tracer, 18F-DCFPyL. The external validation cohort consisted of 157 men from the Prostate Cancer Network Netherlands who underwent 18F-DCFPyL PET/CT to guide salvage therapies after RP. The nomogram of Rauscher et al (predicting a positive scan) showed accurate prediction of 50–80% (discrimination 0.68, 95% confidence interval [CI] 0.59–0.76). The nomogram of Luiting et al (predicting recurrence outside the prostatic fossa) showed accurate prediction for predicted probability values between 15% and 65%, with a small degree of overestimation for predicted probability values between 30% and 50% (discrimination 0.74, 95% CI 0.28–1.24). According to calibration curves, discrimination results, and decision curve analysis, we conclude that clinicians can use these 68Ga-PSMA–based nomograms to predict 18F-DCFPyL PET/CT outcome. These nomograms improve shared decision-making in determining the optimal time to initiate PSMA PET/CT–guided salvage therapies. Patient summary: Prediction tools developed for prostate scans (positron emission tomography, PET) using one type of radioactive tracer (chemicals labeled with gallium-68) are also accurate in predicting scan findings with another tracer (a chemical labeled with fluorine-18). Our study confirms that these tools can be used to guide decisions on the timing of treatments for prostate cancer recurrence.

INTRODUCTION: The additional diagnostic value of dye-based chromoendosocpy (CE) for surveillance of patients with Lynch syndrome is subject of debate.METHODS: To clarify this debate, we performed an individual patient data meta-analysis of randomized studies that compared CE with WLE for the detection of adenomas in patients with Lynch syndrome.RESULTS: Three randomized studies comprising 533 patients were included. The adenoma detection rate was 74/265 (28%) in patients randomized to WLE compared with 83/266 (31%) in patients randomized to CE (odds ratio 1.17; 95% confidence interval 0.81-1.70).DISCUSSION: Based on low-quality evidence, CE showed no apparent increase in adenoma detection compared to WLE during surveillance of patients with Lynch syndrome.

ObjectiveDespite regular colonoscopy surveillance, colorectal cancers still occur in patients with Lynch syndrome. Thus, detection of all relevant precancerous lesions remains very important. The present study investigates Linked Colour imaging (LCI), an image-enhancing technique, as compared with high-definition white light endoscopy (HD-WLE) for the detection of polyps in this patient group.DesignThis prospective, randomised controlled trial was performed by 22 experienced endoscopists from eight centres in six countries. Consecutive Lynch syndrome patients ≥18 years undergoing surveillance colonoscopy were randomised (1:1) and stratified by centre for inspection with either LCI or HD-WLE. Primary outcome was the polyp detection rate (PDR).ResultsBetween January 2018 and March 2020, 357 patients were randomised and 332 patients analysed (160 LCI, 172 HD-WLE; 6 excluded due to incomplete colonoscopies and 19 due to insufficient bowel cleanliness). No significant difference was observed in PDR with LCI (44.4%; 95% CI 36.5% to 52.4%) compared with HD-WLE (36.0%; 95% CI 28.9% to 43.7%) (p=0.12). Of the secondary outcome parameters, more adenomas were found on a patient (adenoma detection rate 36.3%; vs 25.6%; p=0.04) and a colonoscopy basis (mean adenomas per colonoscopy 0.65 vs 0.42; p=0.04). The median withdrawal time was not statistically different between LCI and HD-WLE (12 vs 11 min; p=0.16).ConclusionLCI did not improve the PDR compared with HD-WLE in patients with Lynch syndrome undergoing surveillance. The relevance of findings more adenomas by LCI has to be examined further.Trial registration numberNCT03344289.

Background Volumetric laser endomicroscopy (VLE) allows for near-microscopic imaging of the superficial esophageal wall and may improve detection of early neoplasia in Barrett’s esophagus (BE). Interpretation of a 6-cm long, circumferential VLE “full scan” may however be challenging for endoscopists. We aimed to evaluate the accuracy of VLE experts in correctly diagnosing VLE full scans of early neoplasia and non-dysplastic BE (NDBE). Methods 29 VLE full scan videos (15 neoplastic and 14 NDBE) were randomly evaluated by 12 VLE experts using a web-based module. Experts were blinded to the endoscopic BE images and histology. The 15 neoplastic cases contained a subtle endoscopically visible lesion, which on endoscopic resection showed high grade dysplasia or cancer. NDBE cases had no visible lesions and an absence of dysplasia in all biopsies. VLE videos were first scored as “neoplastic” or “NDBE.” If neoplastic, assessors located the area most suspicious for neoplasia. Primary outcome was the performance of VLE experts in differentiating between non-dysplastic and neoplastic full scan videos, calculated by accuracy, sensitivity, and specificity. Secondary outcomes included correct location of neoplasia, interobserver agreement, and level of confidence. Results VLE experts correctly labelled 73 % (95 % confidence interval [CI] 67 % – 79 %) of neoplastic VLE videos. In 54 % (range 27 % – 66 %) both neoplastic diagnosis and lesion location were correct. NDBE videos were consistent with endoscopic biopsies in 52 % (95 %CI 46 % – 57 %). Interobserver agreement was fair (kappa 0.28). High level of confidence was associated with a higher rate of correct neoplastic diagnosis (81 %) and lesion location (73 %). Conclusions Identification of subtle neoplastic lesions in VLE full scans by experts was disappointing. Future studies should focus on improving methodologies for reviewing full scans, development of refined VLE criteria for neoplasia, and computer-aided diagnosis of VLE scans.