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This study compares three different pretreatment protocols for the immunohistochemical detection of 5-methylcytosine (5-mC) and 5-hydroxymethylcytosine (5-hmC) in nuclear DNA. The human biological samples analyzed included formalin-fixed and paraffin-embedded (FFPE) normal squamous epithelium, ethanol-fixed cultured cells, and metaphase chromosomes. The antigen retrieval methods included low pH Citrate and high pH Tris–ethylenediaminetetraacetic acid (EDTA) protocols, as well as a method using Pepsin pretreatment combined with HCl for DNA denaturation. A gradual increase in the detection levels of 5-mC and 5-hmC was observed when going from Citrate via Tris/EDTA to Pepsin/HCl retrieval. While the Citrate retrieval protocol was the least efficient for the detection of 5-mC and 5-hmC, it did preserve nuclear morphology and enabled visualization of differences in intra- and internuclear distribution patterns in tissue and cell culture samples by single- and double-fluorescence detection. Quantification of (hydroxy)methylation levels in FFPE material demonstrated a significant heterogeneity and differences in 5-mC and 5-hmC levels within and between nuclei in the different compartments of normal squamous epithelium. It was concluded that immunohistochemical detection of 5-mC and 5-hmC enables the correlation of these DNA modifications with histomorphological features in heterogeneous tissues, but this is influenced by different pretreatment protocols that must be carefully chosen to allow an appropriate interpretation of these epigenetic switches.

BACKGROUND: Response rates of immune checkpoint inhibitor (ICI) therapy for recurrent and/or metastatic head and neck squamous cell carcinoma (R/M HNSCC) are low. PATIENTS AND METHODS: This retrospective multicentre cohort study evaluates the predictive and prognostic value of weight loss and changes in body composition prior and during therapy. Patient, tumor, and treatment characteristics of 98 patients were retrieved, including neutrophil and platelet-lymphocyte-ratio (NLR and PLR). Programmed death-ligand 1 (PD-L1) expression was determined on residual material. Cachexia was defined according to Fearon et al. (2011). Skeletal muscle (SM), visceral adipose tissue (VAT), and subcutaneous adipose tissue (SAT) were evaluated on computed tomography scans at the third lumbar vertebrae level. Univariable and multivariable regression analyses were performed for 6 months progression free survival (PFS6m) and overall survival (OS). RESULTS: Significant early weight loss (>2%) during the first 6 weeks of therapy was shown in 34 patients (35%). This patient subgroup had a significantly higher NLR and PLR at baseline. NLR and PLR were inversely correlated with SM and VAT index. Independent predictors of PFS6m were lower World Health Organization performance status (HR 0.16 [0.04-0.54] p = 0.003), higher baseline SAT index (HR 1.045 [1.02-1.08] p = 0.003), and weight loss 2% early weight loss remained a predictor of OS, independent of PD-L1 expression (HR 2.09 [1.11-3.92] p = 0.02, HR 2.18 [1.13-4.21] p = 0.02). CONCLUSION: We conclude that the combination of cachexia at baseline and weight loss during ICI therapy is associated with worse OS in R/M HNSCC patients, independent of PD-L1 expression. ispartof: CANCER MEDICINE vol:12 issue:7 pages:7699-7712 ispartof: location:United States status: published

Background No definitive largescale data exist evaluating the role of pathologically defined regression changes within the primary tumour and lymph nodes (LN) of resected oesophagogastric (OG) adenocarcinoma following neoadjuvant chemotherapy and the impact on survival. Methods Data and samples from two large prospective randomised trials (UK MRC OE05 and ST03) were pooled. Stained slides were available for central pathology review from 1619 patients. Mandard tumour regression grade (TRG) and regression of tumour within LNs (LNR: scored as present/absent) were assessed and correlated with overall survival (OS) using a Cox regression model. An exploratory analysis to define subgroups with distinct prognoses was conducted using a classification and regression tree (CART) analysis. Results Neither trial demonstrated a relationship between TRG score and the presence or absence of LNR. In univariable analysis, lower TRG, lower ypN stage, lower ypT stage, presence of LNR, presence of well/moderate tumour differentiation, and absence of tumour at resection margin were all associated with better OS. However, the multivariable analysis demonstrated that only ypN, ypT, grade of differentiation and resection margin (R0) were independent indicators of prognosis. Exploratory CART analysis identified six subgroups with 3-year OS ranging from 83% to 22%; with ypN stage being the most important single prognostic variable. Conclusions Pathological LN stage within the resection specimen was the single most important determiner of survival. Our results suggest that the assessment of regression changes within the primary tumour or LNs may not be necessary to define the prognosis further.

BACKGROUND: Several pivotal studies and international guidelines on the perioperative management of rectal cancer have been published. However, little is known about the current state of perioperative management of rectal cancer patients in clinical practice worldwide.METHODS: An online survey including 13 questions focusing on key topics related to the perioperative management of patients with rectal cancer was conducted among colorectal surgeons registered within the database of the Research Institute Against Digestive Cancer (IRCAD).RESULTS: A total of 535 respondents from 89 countries participated in the survey. Most surgeons worked in the European region (40.9%). Two hundred and fifty-four respondents (47.5%) performed less than 25% of surgical procedures laparoscopically. The most commonly used definition of the upper limit of the rectum was a fixed distance from the anal verge (23.4%). Magnetic resonance imaging was used to define the upper limit of the rectum by 258 respondents (48.2%). During total mesorectal excision (TME), 301 respondents (56.3%) used a high-tie technique. The most commonly constructed anastomosis was an end-to-end anastomosis (68.2%) with the majority of surgeons performing a leak test intraoperatively (88.9%). A total of 355 respondents (66.4%) constructed a diverting ostomy, and the majority of these surgeons constructed an enterostomy (82%). A total of 208 respondents (39.3%) closed a stoma within 8 weeks. Lastly, 135 respondents (25.2%) introduced a solid diet on postoperative day 1.CONCLUSION: There is considerable heterogeneity in the perioperative management of rectal cancer patients worldwide with several discrepancies between current international practice and recommendations from international guidelines. To achieve worldwide standardization in rectal cancer care, further research is needed to elucidate the cause of this heterogeneity and find ways of improved implementation of best practice recommendations.

BACKGROUND: Cyclin E1 (CCNE1) is a potential predictive marker and therapeutic target in tubo-ovarian high-grade serous carcinoma (HGSC). Smaller studies have revealed unfavorable associations for CCNE1 amplification and CCNE1 overexpression with survival, but to date no large-scale, histotype-specific validation has been performed. The hypothesis was that high-level amplification of CCNE1 and CCNE1 overexpression, as well as a combination of the two, are linked to shorter overall survival in HGSC. METHODS: Within the Ovarian Tumor Tissue Analysis consortium, amplification status and protein level in 3029 HGSC cases and mRNA expression in 2419 samples were investigated. RESULTS: High-level amplification (>8 copies by chromogenic in situ hybridization) was found in 8.6% of HGSC and overexpression (>60% with at least 5% demonstrating strong intensity by immunohistochemistry) was found in 22.4%. CCNE1 high-level amplification and overexpression both were linked to shorter overall survival in multivariate survival analysis adjusted for age and stage, with hazard stratification by study (hazard ratio [HR], 1.26; 95% CI, 1.08-1.47, p = .034, and HR, 1.18; 95% CI, 1.05-1.32, p = .015, respectively). This was also true for cases with combined high-level amplification/overexpression (HR, 1.26; 95% CI, 1.09-1.47, p = .033). CCNE1 mRNA expression was not associated with overall survival (HR, 1.00 per 1-SD increase; 95% CI, 0.94-1.06; p = .58). CCNE1 high-level amplification is mutually exclusive with the presence of germline BRCA1/2 pathogenic variants and shows an inverse association to RB1 loss. CONCLUSION: This study provides large-scale validation that CCNE1 high-level amplification is associated with shorter survival, supporting its utility as a prognostic biomarker in HGSC. ispartof: CANCER vol:129 issue:5 pages:697-713 ispartof: location:United States status: published

INTRODUCTION: Serous ovarian carcinomas constitute the largest group of epithelial ovarian cancer (60%-75%) and are further classified into high- and low-grade serous carcinoma. Low-grade serous carcinoma (LGSC) is a relatively rare subtype (approximately 5% of serous carcinomas) and epidemiologic studies of large cohorts are scarce. With the present study we aimed to report trends in stage, primary treatment and relative survival of LGSC of the ovary in a large cohort of patients in an effort to identify opportunities to improve clinical practice and outcome of this relatively rare disease.MATERIAL AND METHODS: Patients diagnosed with LGSC between 2000 and 2019 were identified from the Netherlands Cancer Registry (n = 855). Trends in FIGO stages and primary treatment were analyzed with the Cochran-Armitage trend test, and differences in and trends of 5-year relative survival were analyzed using multivariable Poisson regression.RESULTS: Over time, LGSC was increasingly diagnosed as stage III (39.9%-59.0%) and IV disease (5.7%-14.4%) and less often as stage I (34.6%-13.5%; p 1 cm residual disease in only 15/252 patients (6%), compared with 17/95 patients (17.9%) after interval surgery. Full cohort 5-year survival was 61% and survival after primary debulking surgery was superior to the outcome following interval debulking surgery (60% vs 34%). Survival following primary debulking surgery without macroscopic residual disease (73%) was better compared with ≤1 cm (47%) and >1 cm residual disease (22%). Survival following interval debulking surgery without macroscopic residual disease (51%) was significantly higher than after >1 cm residual disease (24%). Except FIGO stage II (85%-92%), survival did not change significantly over time.CONCLUSIONS: Over the years, LGSC has been diagnosed as FIGO stage III and stage IV disease more often and interval debulking surgery has been increasingly preferred over primary debulking in these patients. Relative survival did not change over time (except for stage II) and worse survival outcomes after interval debulking surgery were observed. The results support the common recommendation to perform primary debulking surgery in patients eligible for primary surgery.

Purpose: Radiation pneumonitis (RP) is one of the common side effects of radiation therapy in the thoracic region. Radiomics and dosiomics quantify information implicit within medical images and radiation therapy dose distributions. In this study we demonstrate the prognostic potential of radiomics, dosiomics, and clinical features for RP prediction. Methods and Materials: Radiomics, dosiomics, dose-volume histogram (DVH) metrics, and clinical parameters were obtained on 314 retrospectively collected and 35 prospectively enrolled patients diagnosed with lung cancer between 2013 to 2019. A radiomics risk score (R score) and dosiomics risk score (D score), as well as a DVH-score, were calculated based on logistic regression after feature selection. Six models were built using different combinations of R score, D score, DVH score, and clinical parameters to evaluate their added prognostic power. Overoptimism was evaluated by bootstrap resampling from the training set, and the prospectively collected cohort was used as the external test set. Model calibration and decision-curve characteristics of the best-performing models were evaluated. For ease of further evaluation, nomograms were constructed for selected models. Results: A model built by integrating all of the R score, D score, and clinical parameters had the best discriminative ability with areas under the curve of 0.793 (95% confidence interval [CI], 0.735-0.851), 0.774 (95% CI, 0.762-0.786), and 0.855 (95% CI, 0.719-0.990) in the training, bootstrapping, and external test sets, respectively. The calibration curve image showed good agreement between the predicted and actual values, with a slope of 1.21 and intercept of –0.04. The decision curve image showed a positive net benefit for the final model based on the nomogram. Conclusions: Radiomic and dosiomic features have the potential to assist with the prediction of RP, and the combination of radiomics, dosiomics, and clinical parameters led to the best prognostic model in the present study.

Gastric cancer (2022). doi:10.1007/s10120-022-01347-0, Published by Springer, Tokyo

Objectives For patients with ductal carcinoma in situ (DCIS), data about the impact of breast MRI at primary diagnosis on the incidence and characteristics of contralateral breast cancers are scarce. Methods We selected all 8486 women diagnosed with primary DCIS in the Netherlands in 2011–2015 from the Netherlands Cancer Registry. The synchronous and metachronous detection of contralateral DCIS (cDCIS) and contralateral invasive breast cancer (cIBC) was assessed for patients who received an MRI upon diagnosis (MRI group) and for an age-matched control group without MRI. Results Nineteen percent of patients received an MRI, of which 0.8% was diagnosed with synchronous cDCIS and 1.3% with synchronous cIBC not found by mammography. The 5-year cumulative incidence of synchronous plus metachronous cDCIS was higher for the MRI versus age-matched control group (2.0% versus 0.9%, p = 0.02) and similar for cIBC (3.5% versus 2.3%, p = 0.17). The increased incidence of cDCIS was observed in patients aged < 50 years (sHR = 4.22, 95% CI: 1.19–14.99), but not in patients aged 50–74 years (sHR = 0.89, 95% CI: 0.41–1.93). Conclusions MRI at primary DCIS diagnosis detected additional synchronous cDCIS and cIBC, and was associated with a higher rate of metachronous cDCIS without decreasing the rate of metachronous cIBC. This finding was most evident in younger patients. Key Points • Magnetic resonance imaging at primary diagnosis of ductal carcinoma in situ detected an additional synchronous breast lesion in 2.1% of patients. • In patients aged younger than 50 years, the use of pre-operative MRI was associated with a fourfold increase in the incidence of a second contralateral DCIS without decreasing the incidence of metachronous invasive breast cancers up to 5 years after diagnosis. • In patients aged over 50 years, the use of pre-operative MRI did not result in a difference in the incidence of a second contralateral DCIS or metachronous invasive breast cancer.

ImportanceSeveral less-invasive staging procedures have been proposed to replace axillary lymph node dissection (ALND) after neoadjuvant chemotherapy (NAC) in patients with initially clinically node-positive (cN+) breast cancer, but these procedures may fail to detect residual disease. Owing to the lack of high-level evidence, it is not yet clear which procedure is most optimal to replace ALND.ObjectiveTo determine the diagnostic accuracy of radioactive iodine seed placement in the axilla with sentinel lymph node biopsy (RISAS), a targeted axillary dissection procedure.Design, Setting, and ParticipantsThis was a prospective, multicenter, noninferiority, diagnostic accuracy trial conducted from March 1, 2017, to December 31, 2019. Patients were included within 14 institutions (general, teaching, and academic) throughout the Netherlands. Patients with breast cancer clinical tumor categories 1 through 4 (cT1-4; tumor diameter 5 cm or extension to the chest wall or skin) and pathologically proven positive axillary lymph nodes (ie, clinical node categories cN1, metastases to movable ipsilateral level I and/or level II axillary nodes; cN2, metastases to fixed or matted ipsilateral level I and/or level II axillary nodes; cN3b, metastases to ipsilateral level I and/or level II axillary nodes with metastases to internal mammary nodes) who were treated with NAC were eligible for inclusion. Data were analyzed from July 2020 to December 2021.InterventionPre-NAC, the marking of a pathologically confirmed positive axillary lymph node with radioactive iodine seed (MARI) procedure, was performed and after NAC, sentinel lymph node biopsy (SLNB) combined with excision of the marked lymph node (ie, RISAS procedure) was performed, followed by ALND.Main Outcomes and MeasuresThe identification rate, false-negative rate (FNR), and negative predictive value (NPV) were calculated for all 3 procedures: RISAS, SLNB, and MARI. The noninferiority margin of the observed FNR was 6.25% for the RISAS procedure.ResultsA total of 212 patients (median [range] age, 52 [22-77] years) who had cN+ breast cancer underwent the RISAS procedure and ALND. The identification rate of the RISAS procedure was 98.2% (223 of 227). The identification rates of SLNB and MARI were 86.4% (197 of 228) and 94.1% (224 of 238), respectively. FNR of the RISAS procedure was 3.5% (5 of 144; 90% CI, 1.38-7.16), and NPV was 92.8% (64 of 69; 90% CI, 85.37-97.10), compared with an FNR of 17.9% (22 of 123; 90% CI, 12.4%-24.5%) and NPV of 72.8% (59 of 81; 90% CI, 63.5%-80.8%) for SLNB and an FNR of 7.0% (10 of 143; 90% CI, 3.8%-11.6%) and NPV of 86.3% (63 of 73; 90% CI, 77.9%-92.4%) for the MARI procedure. In a subgroup of 174 patients in whom SLNB and the MARI procedure were successful and ALND was performed, FNR of the RISAS procedure was 2.5% (3 of 118; 90% CI, 0.7%-6.4%), compared with 18.6% (22 of 118; 90% CI, 13.0%-25.5%) for SLNB (P P = .03).Conclusions and RelevanceResults of this diagnostic study suggest that the RISAS procedure was the most feasible and accurate less-invasive procedure for axillary staging after NAC in patients with cN+ breast cancer.

OBJECTIVE: To analyze the relationship between negative lymph node (LNneg) size as a possible surrogate marker of the host antitumor immune response and overall survival (OS) in esophageal cancer (EC) patients.BACKGROUND: Lymph node (LN) status is a well-established prognostic factor in EC patients. An increased number of LNnegs is related to better survival in EC. Follicular hyperplasia in LNneg is associated with better survival in cancer-bearing mice and might explain increased LN size.METHODS: The long axis of 304 LNnegs was measured in hematoxylin-eosin stained sections from resection specimens of 367 OE02 trial patients (188 treated with surgery alone (S), 179 with neoadjuvant chemotherapy plus surgery (C+S)) as a surrogate of LN size. The relationship between LNneg size, LNneg microarchitecture, clinicopathological variables, and OS was analyzed.RESULTS: Large LNneg size was related to lower pN category (P = 0.01) and lower frequency of lymphatic invasion (P = 0.02) in S patients only. Irrespective of treatment, (y)pN0 patients with large LNneg had the best OS. (y)pN1 patients had the poorest OS irrespective of LNneg size (P < 0.001). Large LNneg contained less lymphocytes (P = 0.02) and had a higher germinal centers/lymphocyte ratio (P = 0.05).CONCLUSIONS: This is the first study to investigate LNneg size in EC patients randomized to neoadjuvant chemotherapy followed by surgery or surgery alone. Our pilot study suggests that LNneg size is a surrogate marker of the host antitumor immune response and a potentially clinically useful new prognostic biomarker for (y)pN0 EC patients. Future studies need to confirm our results and explore underlying biological mechanisms.

The registration of multi-source radiation oncology data is a time-consuming and labour-intensive procedure. The standardisation of data collection offers the possibility for the acquisition of quality data for research and clinical purposes. With this study, we present an overview of the different tumour group data lists in the Dutch national proton therapy registry. Furthermore, as a representative example of the workings of these different tumour-specific knowledge graphs, we present the FAIR (Findable, Accessible, Interoperable, Reusable) data principles-compliant knowledge graph approach describing the head and neck tumour variables using radiotherapy domain ontologies and semantic web technologies. Our goal is to provide the radiotherapy community with a flexible and interoperable data model for data exchange between centres. We highlight data variables that are needed for models used in the model-based approach (MBA), which ensures a fair selection of patients that will benefit most from proton therapy.

INTRODUCTION: In current renal transplant pathology practice interstitial fibrosis is visually assessed in categories according to the Banff classification. As this has a moderate reproducibility, which is little ameliorated by morphometric analysis, we investigated whether visual renal fibrosis assessment is feasible on a continuous scale, i.e. as percentage affected area of the cortex.METHODS: Protocol renal biopsies taken at transplantation (n=125), three (n=73) and twelve months (n=88) after transplantation were visually scored in categories (Banff), and percentages for interstitial fibrosis (ci). Interobserver variation (ICC and weighted κ) was assessed, and morphometric analysis on Sirus Red stained sections was performed. Correlations between the different methods and their association with donor age and eGFR 1 year and 5 year post transplant were analyzed using Pearson's or Spearman's rho.RESULTS: Interobserver agreement was equivalent for Banffci and %ci (κ0.713 vs. ICC 0.792), and for BanffIF/TA and %IF/TA (κ0.615 vs. ICC 0.743). Both Banffci and %ci were associated with Sirius Red morphometry in three and twelve month. With all three methods, a significant correlation was found between donor age and fibrosis in the implantation biopsy, and between fibrosis in the 12 month biopsy and eGFR at 1 and 5 years (eGFR at 1 year: Sirius Red ρ-0.487, %ci ρ-0.393, Banffci ρ-0.413, all pCONCLUSION: Interstitial fibrosis assessment on a continuous scale can be used next to scoring in categories according to the Banff classification in protocol renal transplant biopsies.

Purpose The Dynamic Imaging Grade of Swallowing Toxicity (DIGEST) is a scale to quantify the severity of pharyngeal dysphagia in head and neck cancer (HNC) patients. This study (1) described the training process of the observers for DIGEST in fiberoptic endoscopic evaluation of swallowing (FEES), (2) determined observer agreement on the DIGEST in FEES, (3) explored the effect of bolus consistency on observer agreement, and 4) explored criterion validity of the DIGEST in FEES. Methods Twenty-seven dysphagic HNC patients were enrolled. Two observers completed a training program for DIGEST in FEES. Observer agreement on the Penetration-Aspiration Scale (PAS), percentage of pharyngeal residue (PPR), and DIGEST grades was determined using linearly weighted Cohen’s kappa coefficient (κ). Results Due to insufficient observer agreement after the first measurement attempt, additional training was organized using an elaborated manual with descriptions of the visuoperceptual variables, thereby improving observer agreement. Intraobserver agreement was almost perfect on the PAS (κ = 0.86–0.88) and PPR (κ = 0.84–0.86). Interobserver agreement was substantial on the PAS (κ = 0.78), almost perfect on the PPR (κ = 0.82), substantial on the safety grade (κ = 0.64), almost perfect on the efficiency grade (κ = 0.85), and substantial on the summary grade (κ = 0.71). Bolus consistency had an effect on observer agreement. A significant correlation was found between DIGEST efficiency grade and EAT-10. Conclusion The DIGEST showed to be a reproducible measurement for FEES in terms of observer agreement. However, agreement between novice observers on the DIGEST was only reached after specific observer-tailored training. Observer agreement should be analyzed by taking bolus consistency into account during training, as this might affect the interpretation of the outcome. A manual with well-defined descriptions can optimize the reproducibility of DIGEST measurements.

Item does not contain fulltext AIMS: Uterine serous carcinoma (USC) is an aggressive subtype of endometrial cancer with high rates of relapse and death. As adjuvant therapy might be beneficial in early-stage disease, the impact of standard complete surgical staging is questioned. Therefore, we wanted to explore the optimal treatment strategy for women diagnosed with USC. MATERIALS AND METHODS: A retrospective multicentre study of women diagnosed with primary USC in the UK and the Netherlands. Treatment strategy in relation to overall survival and progression-free survival was recorded and evaluated with Kaplan-Meier and Cox regression analysis. Furthermore, primary surgical staging and/or adjuvant treatment in relation to patterns of recurrence were evaluated. RESULTS: In total, 272 women with a median age of 70 years were included. Most patients presented with International Federation of Gynecology and Obstetrics (FIGO) stage I disease (44%). Overall, 48% of patients developed recurrent disease, most (58%) with a distant component. Women treated with chemotherapy showed significantly better overall survival (hazard ratio 0.50, 95% confidence interval 0.31-0.81; P = 0.005) and progression-free survival (hazard ratio 0.48, 95% confidence interval 0.28-0.80; P = 0.04) in multivariable analysis. Furthermore, even in surgically staged women with FIGO stage IA disease, a high recurrence rate of 42% was seen. CONCLUSION: Women with USC who received adjuvant chemotherapy showed better survival rates compared with those who received other or no adjuvant treatment. The benefit of adjuvant chemotherapy was observed across all tumour stages, including surgically staged FIGO stage IA. These data question the role of surgical staging in the absence of macroscopic disease in USC. 01 februari 2023

Introduction. One of the major changes in the revised (2018) FIGO-staging system is the addition of stage IIIC to the previously used 2009 system. We evaluated the prognostic value of positive pelvic and/or para-aortic lymph nodes in patients with cervical cancer.Methods. A nationwide retrospective cohort study was performed by analyzing data from the Netherlands Cancer Registry. All patients newly diagnosed with stage IB-IVA between 2005 and 2018 were identified. Three-year, 5-year and 15-year overall survival (OS) rates were estimated with the Kaplan-Meier method.Results. Of the included 6082 patients, 1740 patients (29%) had pelvic and/or para-aortic lymph node metas-tases. For patients with FIGO 2009 stage IB-IB1-IIA-IIA1 and stage IB2-IIA2-IIB with pelvic and/or para-aortic lymph node metastases the OS was significantly different (p < 0.001 and p = 0.009), with a 5-year OS of 77% and 67%, compared with 92% and 74% for women without lymph node metastases. For FIGO 2009 stage IIIA-IIIB-IVA with and without lymph node metastases, survival rates are not significantly different (p = 0.064). For FIGO 2018 stage IIIC the 3y-OS, 5y-OS and 15-year OS are 72%, 65% and 59% respectively. Survival rates of IIIC diagnosed based on imaging (IIICr) are significantly impaired compared to stage IIIC diagnosed based on pathology (IIICp) (p < 0.001).Conclusion. Patients with FIGO 2009 stage IB-IIB cervical cancer with pelvic and/or para-aortic lymph node metastases have significantly impaired survival compared to patients without metastases. Survival rates of patients with FIGO 2009 stage IIIA-IVA are not affected by lymph node metastases.(c) 2023 Published by Elsevier Inc.

BACKGROUND AND PURPOSE: Dose-escalation in rectal cancer (RCa) may result in an increased complete response rate and thereby enable omission of surgery and organ preservation. In order to implement dose-escalation, it is crucial to develop a technique that allows for accurate image-guided radiotherapy. The aim of the current study was to determine the performance of a novel liquid fiducial marker (BioXmark®) in RCa patients during the radiotherapy course by assessing its positional stability on daily cone-beam CT (CBCT), technical feasibility, visibility on different imaging modalities and safety.MATERIALS AND METHODS: Prospective, non-randomized, single-arm feasibility trial with inclusion of twenty patients referred for neoadjuvant chemoradiotherapy for locally advanced RCa. Primary study endpoint was positional stability on CBCT. Furthermore, technical aspects, safety and clinical performance of the marker, such as visibility on different imaging modalities, were evaluated.RESULTS: Seventy-four markers from twenty patients were available for analysis. The marker was stable in 96% of the cases. One marker showed clinically relevant migration, one marker was lost before start of treatment and one marker was lost during treatment. Marker visibility was good on computed tomography (CT) and CBCT, and moderate on electronic portal imaging (EPI). Marker visibility on magnetic resonance imaging (MRI) was poor during response evaluation.CONCLUSION: The novel liquid fiducial marker demonstrated positional stability. We provide evidence of the feasibility of the novel fiducial marker for image-guided radiotherapy on daily cone beam CT for RCa patients.

ObjectiveComplication rates after cytoreductive surgery are important quality indicators for hospitals that treat patients with advanced-stage ovarian cancer. Case-mix factors are patient and tumor characteristics that may influence hospital outcomes such as the complication rates. Currently, no case-mix adjustment model exists for complications after cytoreductive surgery; therefore, it is unclear whether hospitals are being compared correctly. This study aims to develop the first case-mix adjustment model for complications after surgery for advanced-stage ovarian cancer, enabling an accurate comparison between hospitals.MethodsThis population-based study included all patients undergoing cytoreductive surgery for advanced-stage ovarian cancer registered in the Netherlands in 2017–2019. Case-mix variables were identified and assessed using logistic regressions. The primary outcome was the composite outcome measure ‘complicated course’. Patients had a complicated course when at least one of the following criteria were met: (1) any complication combined with a prolonged length of hospital stay; (2) complication requiring reintervention; (3) any complication with a prolonged length of stay in the intensive care unit; or (4) 30-day mortality or in-hospital mortality during admission following surgery. Inter-hospital variation was analyzed using univariable and multivariable logistic regressions and visualized using funnel plots.ResultsA total of 1822 patients were included, of which 10.7% (n=195) had a complicated course. Comorbidity and tumor stage had a significant impact on complicated course rates in multivariable logistic regression. Inter-hospital variation was not significant for case-mix factors. Complicated course rates ranged between 2.2% and 29.1%, and case-mix adjusted observed/expected ratios ranged from 0.20 to 2.67 between hospitals. Three hospitals performed outside the confidence intervals for complicated course rates. These hospitals remained outliers after case-mix adjustment.ConclusionThere is variation between hospitals regarding complicated course rates after cytoreductive surgery for ovarian cancer in the Netherlands. While comorbidity and tumor stage significantly affected the complicated course rates, adjusting for case-mix factors did not significantly affect hospital outcomes. The limited impact of case-mix adjustment could be a result of the Dutch centralized healthcare model.

BACKGROUND: Chronic tinnitus can have an immense impact on quality of life. Despite recent treatment advances, many tinnitus patients remain refractory to them. Preclinical and clinical evidence suggests that deep brain stimulation (DBS) is a promising treatment to suppress tinnitus. In rats, it has been shown in multiple regions of the auditory pathway that DBS can have an alleviating effect on tinnitus. The thalamic medial geniculate body (MGB) takes a key position in the tinnitus network, shows pathophysiological hallmarks of tinnitus, and is readily accessible using stereotaxy. Here, a protocol is described to evaluate the safety and test the therapeutic effects of DBS in the MGB in severe tinnitus sufferers.METHODS: Bilateral DBS of the MGB will be applied in a future study in six patients with severe and refractory tinnitus. A double-blinded, randomized 2 × 2 crossover design (stimulation ON and OFF) will be applied, followed by a period of six months of open-label follow-up. The primary focus is to assess safety and feasibility (acceptability). Secondary outcomes assess a potential treatment effect and include tinnitus severity measured by the Tinnitus Functional Index (TFI), tinnitus loudness and distress, hearing, cognitive and psychological functions, quality of life, and neurophysiological characteristics.DISCUSSION: This protocol carefully balances risks and benefits and takes ethical considerations into account. This study will explore the safety and feasibility of DBS in severe refractory tinnitus, through extensive assessment of clinical and neurophysiological outcome measures. Additionally, important insights into the underlying mechanism of tinnitus and hearing function might be revealed.TRIAL REGISTRATION: ClinicalTrials.gov NCT03976908 (6 June 2019).

BACKGROUND: This study aims to investigate the relationship between cancer cachexia and oropharyngeal dysphagia (OD) in patients with head and neck cancer (HNC) prior to chemoradiotherapy or bioradiotherapy (CRT/BRT).METHODS: A prospective cohort study with patients with HNC undergoing CRT/BRT (2018-2021) was conducted. Body composition and skeletal muscle function were evaluated using bioelectrical impedance analysis, handgrip strength, and the short physical performance battery (SPPB). The M. D. Anderson Dysphagia Inventory (MDADI), Eating Assessment Tool (EAT)-10 questionnaire, and patient characteristics were collected. A standardized videofluoroscopic swallowing study was offered to patients.RESULTS: Sixty-six patients were included. Twenty-six patients scored EAT-10 ≥ 3 and seventeen were cachectic. ACE-27 score >1, cachexia, abnormal SPPB-derived repeated chair-stand test, lower MDADI scores, and higher overall stage grouping showed potential predictive value (p ≤ 0.10) for EAT-10 ≥ 3. Using multivariable regression analysis, only cachexia remained a significant predictor of EAT-10 ≥ 3 (HR 9.000 [95%CI 2.483-32.619], p = 0.001).CONCLUSION: Cachexia independently predicted the presence of patient-reported OD.

KRAS mutations (KRASmut ), PIK3CAmut , BRAFmut , and deficient DNA mismatch repair (dMMR) have been associated with the Warburg effect. We previously reported differential associations between early-life energy balance-related factors (height, energy restriction, body mass index [BMI]) and colorectal cancer (CRC) subtypes based on the Warburg effect. We now investigated associations of early-life energy balance-related factors and the risk of CRC subgroups based on mutation and MMR status. Data from the Netherlands Cohort Study was used. KRASmut , PIK3CAmut, BRAFmut, and MMR status were available for 2349 CRC cases, and complete covariate data for 1934 cases and 3911 subcohort members. Multivariable-adjusted Cox regression was used to estimate associations of height, energy restriction proxies (exposure to Dutch Hunger Winter, Second World War, Economic Depression), and early adult BMI (age 20 years) with risk of CRC based on individual molecular features and combinations thereof (all-wild-type+MMR-proficient [pMMR]; any-mutation/dMMR). Height was positively associated with any-mutation/dMMR CRC but not all-wild-type+pMMR CRC, with the exception of rectal cancer in men, and with heterogeneity in associations observed for colon cancer in men (p-heterogeneity = 0.049) and rectal cancer in women (p-heterogeneity = 0.014). Results on early-life energy restriction proxies in relation to the risk of CRC subgroups did not show clear patterns. Early adult BMI was positively, but not significantly, associated with KRASmut colon cancer in men and with BRAFmut and dMMR colon cancer in women. Our results suggest a role of KRASmut , PIK3CAmut , BRAFmut , and dMMR in the etiological pathway between height and CRC risk. KRASmut might potentially play a role in associations of early adult BMI with colon cancer risk in men, and BRAFmut and dMMR in women.

Purpose Reduced temporal muscle thickness (TMT) has recently been postulated as a prognostic imaging marker and an objective tool to assess patients frailty in glioblastoma. Our aim is to investigate the correlation of TMT and systemic muscle loss to confirm that TMT is an adequate surrogate marker of sarcopenia in newly diagnosed glioblastoma patients. Methods TMT was assessed on preoperative MR-images and skeletal muscle area (SMA) was assessed at the third lumbar vertebra on preoperative abdominal CT-scans. Previous published TMT sex-specific cut-off values were used to classify patients as ‘patient at risk of sarcopenia’ or ‘patient with normal muscle status’. Correlation between TMT and SMA was assessed using Spearman’s rank correlation coefficient. Results Sixteen percent of the 245 included patients were identified as at risk of sarcopenia. The mean SMA of glioblastoma patients at risk of sarcopenia (124.3 cm2, SD 30.8 cm2) was significantly lower than the mean SMA of patients with normal muscle status (146.3 cm2, SD 31.1 cm2, P P < .001), and a strong association in the patients at risk of sarcopenia (Spearman’s rho 0.678, P Conclusion Our results confirm the use of TMT as a surrogate marker of total body skeletal muscle mass in glioblastoma, especially in frail patients at risk of sarcopenia. TMT can be used to identify patients with muscle loss early in the disease process, which enables the implementation of adequate intervention strategies.

Neuronal heterogeneity has been established as a pillar of higher central nervous system function, but glial heterogeneity and its implications for neural circuit function are poorly understood. Here we show that the adult mouse dentate gyrus (DG) of the hippocampus is populated by molecularly distinct astrocyte subtypes that are associated with distinct DG layers. Astrocytes localized to different DG compartments also exhibit subtype-specific morphologies. Physiologically, astrocytes in upper DG layers form large syncytia, while those in lower DG compartments form smaller networks. Astrocyte subtypes differentially express glutamate transporters, which is associated with different amplitudes of glutamate transporter-mediated currents. Key molecular and morphological features of astrocyte diversity in the mice DG are conserved in humans. This adds another layer of complexity to our understanding of brain network composition and function, which will be crucial for further studies on astrocytes in health and disease.

BACKGROUND: Cancer trial accrual is a national priority, yet up to 20% of trials fail to accrue. Trial eligibility criteria growth may be associated with accrual failure. We sought to quantify eligibility criteria growth within National Cancer Institute (NCI)-affiliated trials and determine impact on accrual.METHODS: Utilizing the Aggregated Analysis of ClinicalTrials.gov, we analyzed phase II/III interventional NCI-affiliated trials initiated between 2008 and 2018. Eligibility criteria growth was assessed via number of unique content words within combined inclusion and exclusion criteria. Association between unique word count and accrual failure was evaluated with multivariable logistic regression, adjusting for known predictors of failure. Medical terms associated with accrual failure were identified via natural language processing and categorized.RESULTS: Of 1197 trials, 231 (19.3%) failed due to low accrual. Accrual failure rate increased with eligibility criteria growth, from 11.8% in the lowest decile (12-112 words) to 29.4% in the highest decile (445-750 words). Median eligibility criteria increased over time, from 214 (IQR [23, 282]) unique content words in 2008 to 417 (IQR [289, 514]) in 2018 (r2 = 0.73, P CONCLUSIONS: Eligibility criteria content growth is increasing dramatically among NCI-affiliated trials and is strongly associated with accrual failure. These findings support national initiatives to simplify eligibility criteria and suggest that further efforts are warranted to improve cancer trial accrual.

STUDY QUESTION For couples with unexplained subfertility and a poor prognosis for natural conception, is 6 months expectant management (EM) inferior to IUI with ovarian stimulation (IUI-OS), in terms of live births? SUMMARY ANSWER In couples with unexplained subfertility and a poor prognosis for natural conception, 6 months of EM is inferior compared to IUI-OS in terms of live births. WHAT IS KNOWN ALREADY Couples with unexplained subfertility and a poor prognosis are often treated with IUI-OS. In couples with unexplained subfertility and a relatively good prognosis for natural conception (>30% in 12 months), IUI-OS does not increase the live birth rate as compared to 6 months of EM. However, in couples with a poor prognosis for natural conception ( STUDY DESIGN, SIZE, DURATION We performed a non-inferiority multicentre randomized controlled trial within the infrastructure of the Dutch Consortium for Healthcare Evaluation and Research in Obstetrics and Gynaecology. We intended to include 1091 couples within 3 years. The couples were allocated in a 1:1 ratio to 6 months EM or 6 months IUI-OS with either clomiphene citrate or gonadotrophins. PARTICIPANTS/MATERIALS, SETTING, METHODS We studied heterosexual couples with unexplained subfertility and a poor prognosis for natural conception ( MAIN RESULTS AND THE ROLE OF CHANCE Between October 2016 and September 2020, we allocated 92 couples to EM and 86 to IUI-OS. The trial was halted pre-maturely owing to slow inclusion. Mean female age was 34 years, median duration of subfertility was 21 months. Couples allocated to EM had a lower live birth rate than couples allocated to IUI-OS (12/92 (13%) in the EM group versus 28/86 (33%) in the IUI-OS group; RR 0.40 90% CI 0.24 to 0.67). This corresponds to an absolute RD of minus 20%; 90% CI: −30% to −9%. The hazard ratio for live birth over time was 0.36 (95% CI 0.18 to 0.70). In the PP analysis, live births rates were 8 of 70 women (11%) in the EM group versus 26 of 73 women (36%) in the IUI-OS group (RR 0.32, 90% CI 0.18 to 0.59; RD −24%, 90% CI −36% to −13%) in line with inferiority of EM. LIMITATIONS, REASONS FOR CAUTION Our trial did not reach the planned sample size, therefore the results are limited by the number of participants. WIDER IMPLICATIONS OF THE FINDINGS This study confirms the results of a previous trial that in couples with unexplained subfertility and a poor prognosis for natural conception, EM is inferior to IUI-OS. STUDY FUNDING/COMPETING INTEREST(S) The trial was supported by a grant of the SEENEZ healthcare initiative. The subsidizing parties were The Dutch Organisation for Health Research and Development (ZonMW 837004023, www.zonmw.nl) and the umbrella organization of 10 health insurers in The Netherlands. E.R.G. receives personal fees from Titus Health care outside the submitted work. M.G. declares unrestricted research and educational grants from Guerbet, Merck and Ferring not related to the presented work, paid to their institution VU medical centre. A.B.H. reports receiving travel and speakers fees from Nordic Pharma and Merck and he is member of the Nordic Pharma ANGEL group and of the Safety Monitoring Board of Womed. C.B.L. reports speakers fee from Inmed and Yingming, and his department receives research grants from Ferring, Merck and Guerbet paid to VU medical centre. B.W.J.M. is supported by a NHMRC Investigator grant (GNT1176437) and reports consultancy for ObsEva and Merck. M.v.W. received a grant from the Netherlands Organisation for Health Research and Development ZonMW (80-8520098-91072). F.M. received two grants from the Netherlands Organisation for Health Research and Development ZonMW (NTR 5599 and NTR 6590). The other authors report no competing interest. TRIAL REGISTRATION NUMBER Dutch Trial register NL5455 (NTR5599) TRIAL REGISTRATION DATE 18 December 2015 DATE OF FIRST PATIENT’S ENROLMENT 26 January 2017

INTRODUCTION: Placental vascular disease, characterized by Maternal Vascular Malperfusion (MVM) lesions, is considered to be the underlying cause of pregnancy complications. Aim is to evaluate the relationship between the cumulative number of MVM lesion types, and adverse pregnancy- and neonatal outcomes.METHODS: This retrospective cohort study included 272 women with singleton gestations who gave birth at a Dutch tertiary hospital between 2017 and 2018 with available placental histopathology reports. Analyzed according to the Amsterdam Placental Workshop Group Consensus Statement, placentas were divided into groups based on the cumulative number of MVM lesions: no lesions (n = 124), 1-2 types (n = 124) and 3-5 types of lesions (n = 24).RESULTS: The proportion of placenta syndrome (PS) was highest (95.8%) in the 3-5 MVM lesions group (p < 0.001). The presence of MVM lesions was highly associated with PS during pregnancy (aOR 6.81, 95% CI 3.76-12.33). Furthermore, every additional type of MVM lesion corresponded with a threefold increased odds for the occurrence of PS (aOR 3.00, 95% CI 2.10-4.29). The group with 3-5 types of MVM lesions showed the highest incidence of adverse neonatal outcomes, lower mean birth weight, prolonged hospitalization, NICU admissions and neonatal deaths (aOR 6.47, 95% CI 0.33-127.68), corresponding with a fourfold increased odds for the occurrence of neonatal death for every additional MVM lesion (aOR 4.19, 95% CI 1.39-12.68).DISCUSSION: A higher number of MVM lesion types is strongly associated with an increased incidence of adverse pregnancy- and neonatal outcomes, indicating that guidelines should focus also on the amount of MVM lesion types for the monitoring/management of subsequent pregnancies.

Background: Orthopedia homeobox (OTP) has shown to be a useful prognostic marker to predict outcome in pulmonary carcinoids, which is also supported by the World Health Organization. However, the discontinuation of the initially used polyclonal antibody and absence of a reliable routinely applicable monoclonal OTP antibody hampers implementation in routine diagnostics. Here, new monoclonal antibodies directed against OTP were developed and verified on formalin-fixed paraffin-embedded tissue of pulmonary neuroendocrine tumors (NETs) for clinical diagnostics. Methods: OTP specific monoclonal antibodies were produced from mice immunised with a recombinant human OTP protein fragment. Enzyme-linked immunosorbent assay (ELISA) positive hybridomas were evaluated using immunohistochemistry (IHC). Following epitope-mapping and isotyping, purified monoclonal antibodies were validated for IHC in formalin-fixed paraffin-embedded tissues, the optimal dilution was determined, and results were cross validated with the OTP polyclonal antibody (HPA039365, Atlas Antibodies). Staining protocols were optimized on two automated staining platforms and performance was harmonized using a tissue microarray (TMA). Results: Two clones (CL11222 and CL11225) were selected for purified monoclonal antibody (mAb) production. Intratumor heterogeneity assessment revealed similar performance for both clones. While clone CL11225 displayed a unique epitope compared to those present in the polyclonal antibody, this clone performed most similar to the polyclonal antibody. Cross-platform assessment revealed an excellent agreement for clone CL11225 while clone CL11222 showed somewhat discordant results on Dako. Conclusions: New monoclonal OTP specific antibodies have been developed and verified on different automated immunohistochemical staining platforms. The OTP specific monoclonal antibodies showed excellent agreement with the often-used polyclonal antibody allowing application in routine diagnostics.

Background and aim: The BRASA patient decision aid (BRASA-PtDA) facilitates shared decision making for breast cancer patients (BCPs) facing a radiotherapy treatment decision. During evaluations, patients indicated the wish for quantitative information on side effects. Therefore, this study assessed BCPs opinion on which and how information on side effects should be incorporated in the BRASA-PtDA. Methods: A workshop was organized with BCPs (n = 9), researchers (n = 5) and clinicians (n = 3). Subsequently, a survey was sent to BCPs (n = 744) investigating the generalisability of the workshop findings, and posing additional questions. The survey entailed multiple choice questions on quality of life themes, the use of a decision aid and risk communication. Results: The workshop revealed BCPs wish for a layered, all encompassing information system. Information on the impact of side effects on daily life was preferred above the risk of these side effects. The survey revealed that important quality of life (QoL) themes were having energy (81%; n = 605), arm function (61%; n = 452), pain (55%; n = 410). Despite the focus on qualitative effects in the workshop, 89% of the survey respondents also wanted to be informed on individualized risks of side effects. 54% Of the survey respondents had never heard of a PtDA. Conclusions: BCPs preferred information on the impact of side effects, but also their individualized risks on side effects. Most important QoL themes were having enough energy, arm function and pain. Consequently, the BRASA-PtDA should be reshaped, starting with quality of life themes, rather than side effects.

AIM: To reduce detrimental opioid-related side effects, minimising the postoperative opioid consumption is needed, especially in older patients. Continuous wound infusion (CWI) with local analgesics seems an effective opioid-sparing alternative. However, the added value of CWI to an enhanced recovery protocol after colorectal cancer (CRC) surgery is unclear. The aim of this study was to evaluate the outcomes of CWI after CRC surgery within a strictly adhered enhanced recovery protocol.METHOD: In this multicentre prospective observational cohort study, patients who underwent CRC surgery between May 2019 and January 2021 were included. Patients were treated with CWI as adjunct to multimodal pain management within an enhanced recovery protocol. Postoperative opioid consumption, pain scores and outcomes regarding functional recovery were evaluated.RESULTS: A cohort of 130 consecutive patients were included, of whom 36.2% were ≥75 years. Postoperative opioids were consumed by 80 (61.5%) patients on postoperative day 0, and by 28 (21.5%), 27 (20.8%), and 18 (13.8%) patients on postoperative day 1, 2, and 3, respectively. Median pain scores were CONCLUSION: In patients treated with CWI, low amounts of postoperative opioid consumption, adequate postoperative pain control, and enhanced recovery were observed. CWI seems a beneficial opioid-sparing alternative and may further improve the outcomes of an enhanced recovery protocol after CRC surgery, which seems especially valuable for older patients.

Introduction KRAS mutations (KRASmut), PIK3CAmut, BRAFmut, and mismatch repair deficiency (dMMR) have been associated with the Warburg-effect. We previously observed differential associations between energy balance-related factors (BMI, clothing-size, physical activity) and colorectal cancer (CRC) subtypes based on the Warburg-effect. We now investigated whether associations between energy balance-related factors and risk of CRC differ between subgroups based on mutation and MMR status. Methods Information on molecular features was available for 2349 incident CRC cases within the Netherlands Cohort Study (NLCS), with complete covariate data available for 1934 cases and 3911 subcohort members. Multivariable-adjusted Cox-regression was used to estimate associations of energy balance-related factors with risk of CRC based on individual molecular features (KRASmut; PIK3CAmut; BRAFmut; dMMR) and combinations thereof (all-wild-type + MMR-proficient (pMMR); any-mutation/dMMR). Results In men, BMI and clothing-size were positively associated with risk of colon, but not rectal cancer, regardless of molecular features subgroups; the strongest associations were observed for PIK3CAmut colon cancer. In women, however, BMI and clothing-size were only associated with risk of KRASmut colon cancer (p-heterogeneityKRASmut versus all-wild-type+pMMR = 0.008). Inverse associations of non-occupational physical activity with risk of colon cancer were strongest for any-mutation/dMMR tumors in men and women, and specifically for PIK3CAmut tumors in women. Occupational physical activity was inversely associated with both combination subgroups of colon cancer in men. Conclusion In men, associations did not vary according to molecular features. In women, a role of KRAS mutations in the etiological pathway between adiposity and colon cancer is suggested, and of PIK3CA mutations between physical activity and colon cancer.

Background and purpose: Deep learning (DL) provides high sensitivity for detecting and identifying errors in pre-treatment radiotherapy quality assurance (QA). This work's objective was to systematically evaluate the impact of different dose comparison and image preprocessing methods on DL model performance for error identification in pre-treatment QA.Materials and methods: For 53 volumetric modulated arc therapy (VMAT) and 69 stereotactic body radiotherapy (SBRT) treatment plans of lung cancer patients, mechanical errors were simulated (MLC leaf positions, monitor unit scaling, collimator rotation). Two classification levels were assessed: error type (Level 1) and error magnitude (Level 2). Portal dose images with and without errors were compared using standard (gamma analysis), simple (absolute/relative dose difference, ratio) and alternative (distance-to-agreement, structural similarity index, gradient) dose comparison methods. For preprocessing, different normalization methods (min/max and mean/standard deviation) and image resolutions (32 × 32, 64 × 64 and 128 × 128) were evaluated. All possible combinations of classification level, dose comparison, normalization method and image size resulted in 144 input datasets for DL networks for error identification.Results: Average accuracy was highest for simple dose comparison methods (Level 1: 97.7%, Level 2: 78.1%) while alternative methods scored lowest (Level 1: 91.6%, Level 2: 71.2%). Mean/stdev normalization particularly improved Level 2 classification. Higher image resolution improved error identification, although for SBRT lower image resolution was also sufficient.Conclusions: The choice of dose comparison method has the largest impact on error identification for pre-treatment QA using DL, compared to image preprocessing. Model performance can improve by using simple dose comparison methods, mean/stdev normalization and high image resolution.

Objective This study aimed to assess the effects of surface electrical stimulation plus voice therapy on voice in dysphonic patients with idiopathic Parkinson's disease. Method Patients were assigned to 3 treatment groups (n = 28 per group) and received daily treatment for 3 weeks on 5 days a week. All three groups received voice therapy (usual care). In addition, two groups received surface electrical stimulation, either motor-level or sensory-level stimulation. A standardised measurement protocol to evaluate therapeutic effects included the Voice Handicap Index and videolaryngostroboscopy. Results Voice Handicap Index and videolaryngostroboscopic assessment showed statistically significant differences between baseline and post-treatment across all groups, without any post-treatment differences between the three groups. Conclusion Intensive voice therapy (usual care) improved idiopathic Parkinson's disease patients' self-assessment of voice impairment and the videolaryngostroboscopic outcome score. However, surface electrical stimulation used as an add-on to usual care did not improve idiopathic Parkinson's disease patients’ self-assessment of voice impairment or the videolaryngostroboscopic outcome scores any further.

BACKGROUND: Artificial intelligence (AI) and deep learning have shown great potential in streamlining clinical tasks. However, most studies remain confined to in silico validation in small internal cohorts, without external validation or data on real-world clinical utility. We developed a strategy for the clinical validation of deep learning models for segmenting primary non-small-cell lung cancer (NSCLC) tumours and involved lymph nodes in CT images, which is a time-intensive step in radiation treatment planning, with large variability among experts.METHODS: In this observational study, CT images and segmentations were collected from eight internal and external sources from the USA, the Netherlands, Canada, and China, with patients from the Maastro and Harvard-RT1 datasets used for model discovery (segmented by a single expert). Validation consisted of interobserver and intraobserver benchmarking, primary validation, functional validation, and end-user testing on the following datasets: multi-delineation, Harvard-RT1, Harvard-RT2, RTOG-0617, NSCLC-radiogenomics, Lung-PET-CT-Dx, RIDER, and thorax phantom. Primary validation consisted of stepwise testing on increasingly external datasets using measures of overlap including volumetric dice (VD) and surface dice (SD). Functional validation explored dosimetric effect, model failure modes, test-retest stability, and accuracy. End-user testing with eight experts assessed automated segmentations in a simulated clinical setting.FINDINGS: We included 2208 patients imaged between 2001 and 2015, with 787 patients used for model discovery and 1421 for model validation, including 28 patients for end-user testing. Models showed an improvement over the interobserver benchmark (multi-delineation dataset; VD 0·91 [IQR 0·83-0·92], p=0·0062; SD 0·86 [0·71-0·91], p=0·0005), and were within the intraobserver benchmark. For primary validation, AI performance on internal Harvard-RT1 data (segmented by the same expert who segmented the discovery data) was VD 0·83 (IQR 0·76-0·88) and SD 0·79 (0·68-0·88), within the interobserver benchmark. Performance on internal Harvard-RT2 data segmented by other experts was VD 0·70 (0·56-0·80) and SD 0·50 (0·34-0·71). Performance on RTOG-0617 clinical trial data was VD 0·71 (0·60-0·81) and SD 0·47 (0·35-0·59), with similar results on diagnostic radiology datasets NSCLC-radiogenomics and Lung-PET-CT-Dx. Despite these geometric overlap results, models yielded target volumes with equivalent radiation dose coverage to those of experts. We also found non-significant differences between de novo expert and AI-assisted segmentations. AI assistance led to a 65% reduction in segmentation time (5·4 min; pINTERPRETATION: We present a clinical validation strategy for AI models. We found that in silico geometric segmentation metrics might not correlate with clinical utility of the models. Experts' segmentation style and preference might affect model performance.FUNDING: US National Institutes of Health and EU European Research Council.

Background: Lung cancer is the leading cause of cancer-related death worldwide, with non-small cell lung cancer (NSCLC) accounting for most cases. While radiotherapy has historically served as a palliative modality in metastatic NSCLC, considerable advances in its technology and the continuous development of cutting-edge therapeutic agents, such as targeted therapy and immune checkpoint inhibitors (ICIs), are increasing its role in the multi-disciplinary management of the disease.Methods: International radiotherapy experts were convened to consider and reach consensuses on the clinical utilities of radiotherapy in metastatic NSCLC, with the aim to provide patient-focused, up to date, evidence-based, recommendations to assist cancer specialists in the management of patients with metastatic NSCLC worldwide.Results: Timely radiotherapy can offer rapid symptom alleviation and allow subsequent aggressive treatment approaches in patients with heavy tumor burden and/or oncologic emergencies. In addition, appropriate incorporation of radiotherapy as concurrent, consolidation, or salvage therapy makes it possible to achieve long-term survival, or even cure, for patients with oligo-metastatic disease. Cranial radiotherapy plays an important role in the management of brain metastasis, potentially augmenting the response and prolonging survival associated with targeted agents and ICIs. However, key questions remain, such as the appropriate choice of radiation techniques, optimal sequence of systemic therapies and radiotherapy, and optimal patient selection for such combination strategies. Although a strong rationale for combining radiotherapy and ICIs exists, its optimal parameters in this setting remain to be established.Conclusions: In the modern era, radiotherapy serves not only as a palliative tool in metastatic NSCLC, but also plays active roles in patients with oligo-focal disease, CNS metastasis and receiving ICIs.

Aims Cutaneous metastases of internal malignancies occur in 1-10% of cancer patients. The diagnosis can sometimes be challenging, especially in cases with an unknown primary cancer. Materials and methods A retrospective case review was performed including all cases of skin metastases from primary internal malignancies diagnosed at the Department of Pathology at the Maastricht University Medical Centre+ from 2007 to 2021. The clinicopathological data were collected and immunohistochemical and molecular diagnostic tests were performed to confirm the primary origin of the metastases. Results We identified 152 cases (71 female; 31 male patients) of cutaneous metastases of internal malignancies. 28 patients (20 women and 8 men) were diagnosed with multiple cutaneous metastases. Among the female patients, the most common primary tumour was breast cancer (50% of the cases), followed by lung (13.6%), gynaecological (7.3%), and gastrointestinal origin (7.3%). Among the male patients, the most common primary sites were gastrointestinal and lung origin (altogether, 50% of the cases). In 19 patients, the cutaneous metastasis was the first presentation of a clinically silent internal malignancy (18.6%), of which most (78.9%) represented metastatic lung carcinomas. Finally, metastasizing patterns were different across tumour types and gender. Conclusion Breast, lung, gastrointestinal, and gynaecologic cancers are the most common primary tumours demonstrating skin metastases. Infrequently, cutaneous metastases can be the first clinically visual manifestation of an underlying not yet diagnosed internal malignancy; therefore, occasional broad immunohistochemical profiling, molecular clonal analysis, and a continuous high level of awareness are necessary for a precise diagnosis of cutaneous metastases of internal malignancies.

PURPOSE: Laborious and time-consuming tumor segmentations are one of the factors that impede adoption of radiomics in the clinical routine. This study investigates model performance using alternative tumor delineation strategies in models predictive of human papillomavirus (HPV) in oropharyngeal squamous cell carcinoma (OPSCC).METHODS: Of 153 OPSCC patients, HPV status was determined using p16/p53 immunohistochemistry. MR-based radiomic features were extracted within 3D delineations by an inexperienced observer, experienced radiologist or radiation oncologist, and within a 2D delineation of the largest axial tumor diameter and 3D spheres within the tumor. First, logistic regression prediction models were constructed and tested separately for each of these six delineation strategies. Secondly, the model trained on experienced delineations was tested using these delineation strategies. The latter methodology was repeated with the omission of shape features. Model performance was evaluated using area under the curve (AUC), sensitivity and specificity.RESULTS: Models constructed and tested using single-slice delineations (AUC/Sensitivity/Specificity: 0.84/0.75/0.84) perform better compared to 3D experienced observer delineations (AUC/Sensitivity/Specificity: 0.76/0.76/0.71), where models based on 4 mm sphere delineations (AUC/Sensitivity/Specificity: 0.77/0.59/0.71) show similar performance. Similar performance was found when experienced and largest diameter delineations (AUC/Sens/Spec: 0.76/0.75/0.65 vs 0.76/0.69/0.69) was used to test the model constructed using experienced delineations without shape features.CONCLUSION: Alternative delineations can substitute labor and time intensive full tumor delineations in a model that predicts HPV status in OPSCC. These faster delineations may improve adoption of radiomics in the clinical setting. Future research should evaluate whether these alternative delineations are valid in other radiomics models.

Objective: To examine the effect of a premenopausal risk-reducing salpingo-oophorectomy (RRSO) in women at increased risk of ovarian cancer on objective and subjective cognition at least 10 years after RRSO.Design: A cross-sectional study with prospective follow-up, nested in a nationwide cohort.Setting: Multicentre in the Netherlands.Population or Sample: 641 women (66% BRCA1/2 pathogenic variant carriers) who underwent either a premenopausal RRSO ≤ age 45 (n = 436) or a postmenopausal RRSO ≥ age 54 (n = 205). All participants were older than 55 years at recruitment.Methods: Participants completed an online cognitive test battery and a questionnaire on subjective cognition. We used multivariable regression analyses, adjusting for age, education, breast cancer, hormone replacement therapy, cardiovascular risk factors and depression.Main Outcome Measures: The influence of RRSO on objective and subjective cognition of women with a premenopausal RRSO compared with women with a postmenopausal RRSO.Results: After adjustment, women with a premenopausal RRSO (mean time since RRSO 18.2 years) performed similarly on objective cognitive tests compared with women with a postmenopausal RRSO (mean time since RRSO 11.9 years). However, they more frequently reported problems with reasoning (odds ratio [OR] 1.8, 95% confidence interval [95% CI] 1.1–3.1) and multitasking (OR 1.9, 95% CI 1.1–3.4) than women with a postmenopausal RRSO. This difference between groups disappeared in an analysis restricted to women of comparable ages (60–70 years).Conclusions: Reassuringly, approximately 18 years after RRSO, we found no association between premenopausal RRSO and objective cognition.

SOX2 expression in high-grade cervical intraepithelial neoplasia (CIN3) and cervical squamous cell carcinoma is increased compared to that in the normal cervical epithelium. However, data on the expression and histological distribution of SOX2 in squamous epithelium during progression of CIN are largely lacking. We studied SOX2 expression throughout the epithelium in 53 cases of CIN1, 2, and 3. In general, SOX2 expression increased and expanded from basal/parabasal to the intermediate/superficial compartment during early stages of progression of CIN. An unexpected, specific expression pattern was found in areas classified as CIN2 and CIN3. This pattern was characterized by the absence or low expression of SOX2 in the basal/parabasal compartment and variable levels in the intermediate and superficial compartments. It was significantly associated with CIN3 (p = 0.009), not found in CIN1 and only seen in part of the CIN2 lesions. When the different patterns were correlated with the genetic make-up and presence of HPV, the CIN3-related pattern contained HPV-positive cells in the basal/parabasal cell compartment that were disomic. This is in contrast to the areas exhibiting the CIN1 and CIN2 related patterns, which frequently exhibited aneusomic cells. Based on their SOX2 localisation pattern, CIN1 and CIN2 could be delineated from CIN3. These data shed new light on the pathogenesis and dynamics of progression in premalignant cervical lesions, as well as on the target cells in the epithelium for HPV infection.

This study aimed to assess the prognostic value of intratumoral CD57+ cells in head and neck squamous cell carcinoma (HNSCC) and to examine the reproducibility of these analyses using QuPath. Pretreatment biopsies of 159 patients with HPV-negative, stage III/IV HNSCC treated with chemoradiotherapy were immunohistochemically stained for CD57. The number of CD57+ cells per mm2 tumor epithelium was quantified by two independent observers and by QuPath, software for digital pathology image analysis. Concordance between the observers and QuPath was assessed by intraclass correlation coefficients (ICC). The correlation between CD57 and clinicopathological characteristics was assessed; associations with clinical outcome were estimated using Cox proportional hazard analysis and visualized using Kaplan-Meier curves. The patient cohort had a 3-year OS of 65.8% with a median follow-up of 54 months. The number of CD57+ cells/mm2 tumor tissue did not correlate to OS, DFS, or LRC. N stage predicted prognosis (OS: HR 0.43, p = 0.008; DFS: HR 0.41, p = 0.003; LRC: HR 0.24, p = 0.007), as did WHO performance state (OS: HR 0.48, p = 0.028; LRC: 0.33, p = 0.039). Quantification by QuPath showed moderate to good concordance with two human observers (ICCs 0.836, CI 0.805–0.863, and 0.741, CI 0.692–0.783, respectively). In conclusion, the presence of CD57+ TILs did not correlate to prognosis in advanced stage, HPV-negative HNSCC patients treated with chemoradiotherapy. Substantial concordance between human observers and QuPath was found, confirming a promising future role for digital, algorithm driven image analysis.

Purpose: Intra-operative radiotherapy (IORT) has been used as a tool to provide a high-dose radiation boost to a limited volume of patients with fixed tumors with a likelihood of microscopically involved resection margins, in order to improve local control. Two main techniques to deliver IORT include high-dose-rate (HDR) brachytherapy, termed 'intra-operative brachytherapy' (IOBT), and electrons, termed 'intra-operative electron radiotherapy' (IOERT), both having very different dose distributions. A recent paper described an improved local recurrence-free survival favoring IOBT over IOERT for patients with locally advanced or recurrent rectal cancer and microscopically irradical resections. Although several factors may have contributed to this result, an important difference between the two techniques was the higher surface dose delivered by IOBT. This article described an adaptation of IOERT technique to achieve a comparable surface dose as dose delivered by IOBT.Material and methods: Two steps were taken to increase the surface dose for IOERT: 1. Introducing a bolus to achieve a maximum dose on the surface, and 2. Re-normalizing to allow for the same prescribed dose at reference depth.Conclusions: We describe and propose an adaptation of IOERT technique to increase surface dose, decreasing the differences between these two techniques, with the aim of further improving local control. In addition, an alternative method of dose prescription is suggested, to consider improved comparison with other techniques in the future.

Mutations in the DNA mismatch repair gene MSH2 are causative of microsatellite instability (MSI) in multiple cancers. Here, we discovered that besides its well-established role in DNA repair, MSH2 exerts a novel epigenomic function in gastric cancer. Unbiased CRISPR-based mass spectrometry combined with genome-wide CRISPR functional screening revealed that in early-stage gastric cancer MSH2 genomic binding is not randomly distributed but rather is associated specifically with tumor-associated super-enhancers controlling the expression of cell adhesion genes. At these loci, MSH2 genomic binding was required for chromatin rewiring, de novo enhancer-promoter interactions, maintenance of histone acetylation levels, and regulation of cell adhesion pathway expression. The chromatin function of MSH2 was independent of its DNA repair catalytic activity but required MSH6, another DNA repair gene, and recruitment to gene loci by the SWI/SNF chromatin remodeler SMARCA4/BRG1. Loss of MSH2 in advanced gastric cancers was accompanied by deficient cell adhesion pathway expression, epithelial-mesenchymal transition, and enhanced tumorigenesis in vitro and in vivo. However, MSH2-deficient gastric cancers also displayed addiction to BAZ1B, a bromodomain-containing family member, and consequent synthetic lethality to bromodomain and extraterminal motif (BET) inhibition. Our results reveal a role for MSH2 in gastric cancer epigenomic regulation and identify BET inhibition as a potential therapy in MSH2-deficient gastric malignancies. Agency for Science, Technology and Research (A*STAR) Ministry of Education (MOE) National Medical Research Council (NMRC) National Research Foundation (NRF) This study was supported by National Medical Research Council grants NMRC/STaR/0026/2015, MOH-000967-00 and OFLCG18May-0003, and A*ccelerate GAP fund ETPL/15-R15 GAP-0021 (to P. Tan) and MOE tier 2 grant (MOE2017-T2-1-105) and NMRC CS-IRG grant (NMRC/CIRG/1481/2017 to S. Li) and SCISSOR (A*STAR IAF-PP) H18/01/a0/020. Funding was also provided by Cancer Science Institute of Singapore, NUS, under the National Research Foundation Singapore and the Singapore Ministry of Education under its Research Centers of Excellence initiative, and block funding from Duke-NUS Medical School. A.M. Nargund is also supported by St. Baldrick's Foundation Research Award. R. Sundar is supported by a National Medical Research Council (NMRC) Fellowship, Singapore. M.J. Fullwood is supported by the RNA Biology Center at the Cancer Science Institute of Singapore, NUS, as part of funding under the Singapore Ministry of Education Academic Research Fund Tier 3 awarded to Daniel Tenen (MOE2014-T3-1-006) and the National Research Foundation Singapore and the Singapore Ministry of Education under its Research Centers of Excellence initiative.

Background Efficient recovery of circulating tumor DNA (ctDNA) depends on the quantity and quality of circulating cell-free DNA (ccfDNA). Here, we evaluated whether various ccfDNA extraction methods routinely applied in Dutch laboratories affect ccfDNA yield, ccfDNA integrity, and mutant ctDNA detection, using identical lung cancer patient–derived plasma samples. Methods Aliquots of 4 high-volume diagnostic leukapheresis plasma samples and one artificial reference plasma sample with predetermined tumor-derived mutations were distributed among 14 Dutch laboratories. Extractions of ccfDNA were performed according to local routine standard operating procedures and were analyzed at a central reference laboratory for mutant detection and assessment of ccfDNA quantity and integrity. Results Mutant molecule levels in extracted ccfDNA samples varied considerably between laboratories, but there was no indication of consistent above or below average performance. Compared to silica membrane–based methods, samples extracted with magnetic beads–based kits revealed an overall lower total ccfDNA yield (−29%; P Conclusions In the Netherlands, we encountered diversity in preanalytical workflows with potential consequences on mutant ctDNA detection in clinical practice. Silica membrane–based methodologies resulted in the highest total ccfDNA yield and are therefore preferred to detect low copy numbers of relevant mutations. Harmonization of the extraction workflow for accurate quantification and sensitive detection is required to prevent introduction of technical divergence in the preanalytical phase and reduce interlaboratory discrepancies.

Background and study aims Neuroendocrine neoplasms (NEN) account for a small number of colorectal neoplasms. Endoscopic detection is essential for diagnosis, treatment and follow-up. Little is known about incidence of NENs in colonoscopy populations or the relationship between clinical, endoscopic and histopathologic features. We evaluated epidemiology, endoscopic and clinical characteristics of colorectal NENs in a population-based cohort. Patients and methods Medical records of NEN cases were cross-linked with the national pathology database from January 2001 to December 2015, in South Limburg County, the Netherlands, covering four endoscopy units. Senior pathologists reviewed and classified NENs using World Health Organization 5th edition (2019) guidelines. Results The number of colorectal NEN diagnoses was stable over time with 0.6 NEN per 1,000 patients. A total of NENs were detected in 85 patients: 65 neuroendocrine tumors (NETs) and 20 poorly differentiated neuroendocrine carcinomas (NECs). Rectal NETs were usually small sessile/submucosal lesions with yellowish (lipoma-like) color. Colonic NETs were larger sessile/submucosal lesions with darker color compared to background. Colorectal NECs presented as large, dark-colored lesions with ulcerated/necrotizing areas. Conclusions Our population-based data point to a stable and low incidence of 0.6 NEN per 1,000 patients in the Netherlands. Rectal NETs mainly present as small sessile yellowish lesions. Colonic NETs present as larger and darker lesions than background mucosa and NECs as darker lesions than background with ulceration/necrosis. Standardized endoscopic characterization of colorectal NENs is necessary to improve recognition of these lesions and provide a basis for evidence-based treatment and surveillance recommendations.

Purpose Prior to radiotherapy combined with chemotherapy (CRT) or biotherapy (BRT) for oropharyngeal squamous cell carcinoma (OPSCC), teeth with poor prognosis that pose a risk for post-RT osteoradionecrosis (ORN) are removed. The effect of tooth loss on body weight loss and tube feeding (TF) dependency during CRT/BRT is unknown. This study aimed to evaluate the effect of incomplete dentition, tooth extractions prior to CRT/BRT, and the subsequent loss of functional units on (1) weight loss during CRT/BRT and (2) the need for TF during CRT/BRT for OPSCC. Methods OPSCC patients treated with CRT/BRT between 2013 and 2016 were included in this retrospective cohort study. Dental status was determined during the dental assessment at first visit and after tooth extractions prior to the start of CRT/BRT. Weight loss during CRT/BRT was scored dichotomously, comparing weight loss > 5% to stable or increased weight. Potential factors associated with weight loss were identified, including patient, tumor, and treatment characteristics. Results Seventy-seven OPSCC patients were included. Forty patients (52%) experienced weight loss > 5% during CRT/BRT. Extractions were performed in 66% of the OPSCC patients. The mean number of extracted teeth was 4.1 ± 5.6 per patient. Tooth extractions prior to CRT/BRT were associated with weight loss > 5% during CRT/BRT (HR 1.130 (95% CI 1.011–1.262), p = 0.031). None of the dental status-related parameters showed any significant associative value for TF during CRT/BRT. Conclusions Pre-CRT/BRT tooth extractions intended to reduce the risk of ORN, are a risk factor for weight loss during CRT/BRT for OPSCC. Trial registration number This study was approved by the medical ethics committee of the MUMC + (METC 2020–1589) on July 28, 2020.

Early-life (childhood to adolescence) energy balance-related factors (height, energy restriction, BMI) have been associated with adult colorectal cancer (CRC) risk. Warburg-effect activation via PI3K/Akt-signaling might explain this link. We investigated whether early-life energy balance-related factors were associated with risk of Warburg-subtypes in CRC. We used immunohistochemistry for six proteins involved in the Warburg-effect (LDHA, GLUT1, MCT4, PKM2, P53, and PTEN) on tissue microarrays of 2399 incident CRC cases from the prospective Netherlands Cohort Study (NLCS). Expression levels of all proteins were combined into a pathway-based sum score and categorized into three Warburg-subtypes (Warburg-low/-moderate/-high). Multivariable Cox-regression analyses were used to estimate associations of height, energy restriction proxies (exposure to Dutch Hunger Winter; Second World War [WWII]; Economic Depression) and adolescent BMI with Warburg-subtypes in CRC. Height was positively associated with colon cancer in men, regardless of Warburg-subtypes, and with Warburg-low colon and Warburg-moderate rectal cancer in women. Energy restriction during the Dutch Hunger Winter was inversely associated with colon cancer in men, regardless of Warburg-subtypes. In women, energy restriction during the Hunger Winter and WWII was inversely associated with Warburg-low colon cancer, whereas energy restriction during the Economic Depression was positively associated with Warburg-high colon cancer. Adolescent BMI was positively associated with Warburg-high colon cancer in men, and Warburg-moderate rectal cancer in women. In conclusion, the Warburg-effect seems to be involved in associations of adolescent BMI with colon cancer in men, and of energy restriction during the Economic Depression with colon cancer in women. Further research is needed to validate these results.

Purpose:Young age at breast cancer diagnosis correlates with unfavorable clinicopathologic features and worse outcomes compared with older women. Understanding biological differences between breast tumors in young versus older women may lead to better therapeutic approaches for younger patients.Experimental Design:We identified 100 patients ≤35 years old at nonmetastatic breast cancer diagnosis who participated in the prospective Young Women's Breast Cancer Study cohort. Tumors were assigned a surrogate intrinsic subtype based on receptor status and grade. Whole-exome sequencing of tumor and germline samples was performed. Genomic alterations were compared with older women (≥45 years old) in The Cancer Genome Atlas, according to intrinsic subtype.Results:Ninety-three tumors from 92 patients were successfully sequenced. Median age was 32.5 years; 52.7% of tumors were hormone receptor-positive/HER2-negative, 28.0% HER2-positive, and 16.1% triple-negative. Comparison of young to older women (median age 61 years) with luminal A tumors (N = 28 young women) revealed three significant differences: PIK3CA alterations were more common in older patients, whereas GATA3 and ARID1A alterations were more common in young patients. No significant genomic differences were found comparing age groups in other intrinsic subtypes. Twenty-two patients (23.9%) in the Young Women's Study cohort carried a pathogenic germline variant, most commonly (13 patients, 14.1%) in BRCA1/2.Conclusions:Somatic alterations in three genes (PIK3CA, GATA3, and ARID1A) occur at different frequencies in young versus older women with luminal A breast cancer. Additional investigation of these genes and associated pathways could delineate biological susceptibilities and improve treatment options for young patients with breast cancer.See related commentary by Yehia and Eng, p. 2209

BACKGROUND: To decrease morbidity caused by anastomotic leakages after a low anterior resection (LAR) with primary anastomosis, a diverting ostomy is often created. Reversal of a diverting ostomy is associated with morbidity, which may result in non-reversal, particularly in the elderly. This study aimed to describe the diverting ostomy-related outcomes in elderly patients with more advanced rectal cancer after LAR.MATERIALS AND METHODS: All rectosigmoid and rectal cancer patients ≥70 years who underwent LAR with primary anastomosis between 2006 and 2019 in the Catharina Hospital (Eindhoven, The Netherlands) were included for analyses. Reversal rates, ostomy-related complications, morbidity and mortality after ostomy reversal, and definitive ostomy rates were evaluated.RESULTS: In total 164 patients were included, of which 150 (91.5%) underwent primary or secondary ostomy creation. Ostomy-related complications were reported in 34.7% (95%-CI 27.1-42.9%). In total, 72.5% (95%-CI 64.2-79.7%) reversed their diverting ostomy. Non-reversal was mostly due to relapsing disease (52.6%). Median time to ostomy reversal was 3.2 months (IQR 2.3-5.0). No or minor complications after ostomy reversal were observed in 84.0% (95%-CI 75.3-90.6%). Over time, ostomy recreation was performed in 15.0% (95%-CI 8.6-23.5%), and ultimately 65.8% (95%-CI 57.8-73.2%) were ostomy-free after the median follow-up of 3.8 years.CONCLUSION: Although most elderly successfully reversed their diverting ostomy after LAR with limited morbidity, attention should be paid for the risk of non-reversal and ostomy recreation over time. Preoperative patient counselling is important in every individual to be able to decide if LAR with primary anastomosis or a permanent end colostomy is preferred.

PURPOSE: Radiomics is an active area of research focusing on high throughput feature extraction from medical images with a wide array of applications in clinical practice, such as clinical decision support in oncology. However, noise in low dose computed tomography (CT) scans can impair the accurate extraction of radiomic features. In this article, we investigate the possibility of using deep learning generative models to improve the performance of radiomics from low dose CTs.METHODS: We used two datasets of low dose CT scans - NSCLC Radiogenomics and LIDC-IDRI - as test datasets for two tasks - pre-treatment survival prediction and lung cancer diagnosis. We used encoder-decoder networks and conditional generative adversarial networks (CGANs) trained in a previous study as generative models to transform low dose CT images into full dose CT images. Radiomic features extracted from the original and improved CT scans were used to build two classifiers - a support vector machine (SVM) and a deep attention based multiple instance learning model - for survival prediction and lung cancer diagnosis respectively. Finally, we compared the performance of the models derived from the original and improved CT scans.RESULTS: Denoising with the encoder-decoder network and the CGAN improved the area under the curve (AUC) of survival prediction from 0.52 to 0.57 (p-value < 0.01). On the other hand, the encoder-decoder network and the CGAN improved the AUC of lung cancer diagnosis from 0.84 to 0.88 and 0.89 respectively (p-value < 0.01). Finally, there are no statistically significant improvements in AUC using encoder-decoder networks and CGAN (p-value = 0.34) when networks trained at 75 and 100 epochs.CONCLUSION: Generative models can improve the performance of low dose CT-based radiomics in different tasks. Hence, denoising using generative models seems to be a necessary pre-processing step for calculating radiomic features from low dose CTs.

The aim of the present study was to re-evaluate 457 renal cell carcinoma (RCC) cases from the Netherlands Cohort Study on Diet and Cancer (NLCS), a large population-based cohort, according to the new 2022 ISUP, Genitourinary Pathology Society and World Health Organisation (WHO) classifications to assess whether newly recognized subtypes of RCC could be found among these cases. These cases were initially evaluated according to the 2004 WHO classification, the Fuhrman grading system and the 3rd version of the Tumor-Node-Metastasis (TNM). Data on tumor size, laterality and date of diagnosis, among other clinicopathological characteristics, were obtained through record linkage with the Netherlands Cancer Registry and the Pathologisch-Anatomisch Landelijk Geautomatiseerd Archief. Digital slides from the NLCS were reviewed by two urogenital pathologists according to the new ISUP grading and the 2022 WHO classification (5th edition). Immunohistochemistry staining for carbonic anhydrase IX was performed on cases with ambiguous morphology. A total of 373 cases of clear cell RCC (ccRCC), 61 cases of papillary RCC (pRCC), 13 cases of chromophobe RCC, 3 cases of collecting duct carcinoma and 4 cases of oncocytoma were identified. The subtyping showed no discrepancy with the previous diagnoses. A comparison of the WHO/ISUP grading to the original Fuhrman grading showed a similar grading in 245 (56.5%) cases of the total ccRCC and pRCC cases. The staging according to the novel TNM classification 8th edition showed a restaging in 286 cases (65.5%). Lymphovascular (microvascular) invasion (LVI) and tumor necrosis (TN) were present in 14.4% and 33.5% of the total number of cases, respectively. Furthermore, the presence of sarcomatoid differentiation in 5.1% and rhabdoid differentiation in 4.2% of the cases was observed. In conclusion, none of the newly accepted and emerging/provisional RCC entities were identified in the NLCS cases, which could be attributed to the high mean age (71.4 years) at diagnosis of the patients included in the present study. A restaging of the NLCS cases using the TNM 8th edition and regrading using ISUP grading was performed, which showed that it is possible to report on newer features, such as sarcomatoid differentiation and LVI, even in an old sample collection.