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Purpose To evaluate the learning curve for locoreginal staging of colon cancer in radiologist trainees. Methods Eighty-eight cases of colon cancer CT were included in this retrospective study. Four senior radiology residents staged the CTs according to TNM classification. Two out of four radiologists received feedback after reading every 20 cases. Radiologic staging was compared with pathologic staging and the learning curve, diagnostic performance, reader confidence and reading time were evaluated and compared between the two groups (feedback vs. no feedback). Generalized estimating equations logistic regression, QICu statistic, ANOVA andttest/Mann-Whitney test were utilized. Results Radiologists demonstrated a significant increase in their performance to distinguish between = T3 and reached an inflection point at 38 cases, with a significant association with increased number of cases reviewed (P < 0.001). Sensitivity (P < 0.001), specificity (P = 0.030) and NPV (P = 0.002) demonstrated significant associations with increased experience. The overall reader's confidence was significantly higher in the group which received feedback (P < 0.001). There was no significant improvement in performance nor in reader's confidence for N staging (N0 vs. >= N1) for all readers. Reading time decreased with experience and showed a significant negative association with experience (P < 0.001). Conclusion Diagnostic performance of senior radiology trainees in differentiating between T2 and T3 colon cancer on CTs improved with increased experience. In contrast, evaluation of lymph node involvement did not improve with more experience. Feedback had no significant effect on improvement of diagnostic performances.

Background: The histological subtype of basal-cell carcinoma (BCC) is often based on a punch biopsy; only a small part is evaluated, possibly leading to misclassification. Consensus on the optimal approach to process punch biopsies is lacking, though accurate subtyping is important for appropriate treatment. Objective: The aim is to investigate whether evaluating 4 levels of a punch biopsy instead of 1 or 2 levels leads to more accurate subtyping of BCC. Methods: In a retrospective study we evaluated 87 punch biopsies of histologically confirmed BCCs. The primary outcome was the proportion of “more aggressive” BCCs (nonsuperficial vs. superficial, infiltrative vs. nodular subtype) that was missed by evaluation on 1 or 2 levels, using 4-level diagnosis as reference standard. Results: Eighty-five cases were available for analysis. Subtyping based on 1 level resulted in discrepancies with 4-level diagnosis in 16.5% of all cases. Underdiagnosis occurred in 14 of 58 nonsuperficial BCCs (24.1%, 95% CI: 13.9–37.2). Seven of 38 nodular BCCs (18.4%, 95% CI: 7.74–34.3) were diagnosed as superficial in 1 level, and 7 of 20 infiltrative BCCs (35%, 95% CI: 15.4–59.2) were diagnosed as superficial (n = 2) or nodular (n = 5) in 1 level. Conclusion: In order to maximize correct subtyping and plan appropriate treatment, we advise to evaluate at least 2, but preferably more, levels of a punch biopsy to determine the BCC subtype.

OBJECTIVES: The trials within cohorts (TwiCs) design aims to improve recruitment efficiency. We conducted the first TwiCs in radiation oncology and described efficiency of the design and generalizability of the results.STUDY DESIGN AND SETTING: In two radiotherapy centers, patients with rectal cancer were asked to participate in a prospective cohort study and to provide broad consent for randomization and patient-reported outcomes (PROs). Consenting patients who met the trial criteria were randomized directly after cohort enrollment. The intervention arm was offered a radiotherapy boost. We evaluated acceptance rate, its impact on sample size, and compared clinical characteristics between trial participants and patients of the Dutch national cancer registry.RESULTS: 128 of the 200 eligible patients (64%) were randomized. Sixty-two patients did not consent (in time) to cohort participation, to broad randomization, or to PROs. Of the 64 patients in the intervention arm, 52 (81%) accepted the intervention. During the trial, the acceptance rate dropped temporarily, after which sample size was adapted. Trial patients were comparable in age, comorbidity, and disease stage to the national rectal cancer population.CONCLUSIONS: The TwiCs design is feasible, allows enrollment of a high proportion of randomizable patients, with positive impact on trial efficiency and generalizability of results in a clinical oncology setting.

Contains fulltext : 225410.pdf (Publisher’s version ) (Closed access) Objective: Determination of the anatomical structures that should be taught to ensure safe and competent practice among general gynaecologists. Study Design: A two-round Delphi survey, face-to-face meeting in focus groups and an individual interview. Participants were medical doctors and trainees from gynaecology, surgery, urology and radiology from academic, non-academic teaching and non-academic, non-teaching hospitals in the Netherlands. Relevant structures were collected from gynaecology surgery atlas based on most common gynaecological surgeries and diseases. These structures were supplemented and critically viewed in focus groups followed by a Delphi survey. In the Delphi survey gynaecologist and trainee's gynaecology from all over the Netherlands scored the items on a Likert scale between 1 (not relevant) and 5 (highly relevant). Consensus was defined when >= 70 % of the panellist scored the item as relevant or very relevant and the average rating was >= 4. Main outcome was clinically relevant anatomical structures. Results: Consensus on 86 clinically relevant anatomical structures divided by nine categories. Conclusions: This study identified a core list of anatomical structures that are relevant to the safe and competent practice of general gynaecologists and that can be used to guide gynaecology postgraduate education. This is the first step in a much wider and complex process of becoming a competent gynaecologist. (C) 2019 Elsevier B.V. All rights reserved.

Background Food frequency questionnaires (FFQs) are a commonly used method to assess dietary intake in epidemiological studies. It is important to evaluate the validity of FFQs in the population of interest.Objective To evaluate the validity of an FFQ for measuring dietary intake in survivors of colorectal cancer (CRC), relative to a 7-day dietary record.Design Dietary intake was assessed 1 year after the end of CRC treatment. Participants first completed a 7-day dietary record and 2 weeks later a 253-item FFQ that measured intake in the preceding month.Participants/setting Data were used from a subsample of participants (n=100) enrolled in an ongoing prospective study (EnCoRe study) in the Netherlands, from 2015 to 2018.Main outcome measures Estimated intakes of total energy, 19 nutrients, and 20 food groups as well as scoring adherence to the dietary recommendations of the World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) were compared between both dietary assessment methods.Statistical analyses performed Means and standard deviations, Spearman rank correlations corrected for within-person variation and total energy, and kappa agreement between quintiles were assessed.Results The median Spearman correlation corrected for within-person variation for nutrients and total energy was 0.60. Correlations >0.50 were found for 15 of 19 nutrients, with highest agreement for vitamin B-12 (0.74), polysaccharides (0.75), and alcohol (0.91). On average, 73% (range=60% to 84%) of participants were classified into the exact same or adjacent nutrient quintile. The median Spearman correlation corrected for within-person variation for food groups was 0.62. Correlations >0.50 were found for 17 of 20 food groups, with highest agreement for cereals and cereal products (0.96), fish (0.96), and potatoes (0.99). The Spearman correlation between total scores of the WCRF/AICR dietary recommendations was 0.53.Conclusions Relative to a 7-day dietary record, the validity of an FFQ for measuring dietary intake among survivors of CRC appeared moderate to good for most nutrients and food groups.

BACKGROUND AND PURPOSE: A higher radiation dose to the heart is known to be associated with increased mortality in non-small cell lung cancer (NSCLC) patients. It is however unknown what the contribution of the heart dose is when other risk factors for mortality are also accounted for. MATERIALS AND METHODS: We constructed and externally validated prediction models of mortality after definitive chemoradiotherapy for NSCLC. Models were developed in 145 stage I-IIIB NSCLC patients. Clinical (performance status, age, gross tumour volume (GTV) combining primary tumour and involved lymph nodes, current smoker) and dosimetric (mean lung (MLD) and heart (MHD) dose) variables were considered. Multivariable logistic regression models predicting 12 and 24 month mortality were built in 5-fold cross-validation. Discrimination and calibration was assessed in 3 external validation datasets containing 878 (via distributed learning), 127 and 96 NSCLC patients. RESULTS: The best discriminating prediction models combined GTV, smoker and/or MHD: bootstrapping AUC (95% CI) of 0.74 (0.66-0.78) and 0.69 (0.55-0.74) at 12 and 24 months. At external validation, the 24 month mortality GTV-smoker-MHD model robustly showed moderate discrimination (AUC = 0.61-0.64 before and 0.64-0.65 after model update) with limited 0.01-0.07 improvement over a GTV-only model, and calibration slope (0.64-0.65). This model can identify patients for whom a MHD reduction may be useful (e.g. PPV = 77%, NPV = 52% (60% cut-off)). CONCLUSIONS: Tumour volume is strongly related to mortality risk in the first 2 years after chemoradiotherapy for NSCLC. Modelling indicates that efforts to reduce cardiac dose may be relevant for small tumours and that smoking has an important negative association with survival. ispartof: RADIOTHERAPY AND ONCOLOGY vol:152 pages:117-125 ispartof: location:Ireland status: published

Synchronous oligometastatic non-small cell lung cancer (NSCLC) definition varies from 1 metastasis in 1 organ (tumour-node-metastasis 8 [TNM8]), 1-3 metastases (European Society for Medical Oncology [ESMO]), ≤3 metastases (including mediastinal nodes [MLN]) after systemic treatment to 3-5 metastases in ongoing trials. A single definition is however needed to design/compare trials. To assess oligometastatic NSCLC definitions used by clinical experts in daily practice and its evolution, we redistributed a 2012 case-based survey (Dooms, the World Congress of Lung Cancer 2013)., info:eu-repo/semantics/published

Highlights • TH-302 combined with RT enhances tumor growth delay in esophageal cancer models. • This combination does not increase normal tissue toxicity on the short and long term. • The increased therapeutic index (1.38) paves the way for future clinical trials., Background and purpose Esophageal cancer incidence is increasing and is rarely curable. Hypoxic tumor areas cause resistance to conventional therapies, making them susceptible for treatment with hypoxia-activated prodrugs (HAPs). We investigated in vivo whether the HAP evofosfamide (TH-302) could increase the therapeutic ratio by sensitizing esophageal carcinomas to radiotherapy without increasing normal tissue toxicity. Materials and methods To assess therapeutic efficacy, growth of xenografted esophageal squamous cell (OE21) or adeno (OE19) carcinomas was monitored after treatment with TH-302 (50 mg/kg, QD5) and irradiation (sham or 10 Gy). Short- and long-term toxicity was assessed in a gut mucosa and lung fibrosis irradiation model, sensitive to acute and late radiation injury respectively. Mice were injected with TH-302 (50 mg/kg, QD5) and the abdominal area (sham, 8 or 10 Gy) or the upper part of the right lung (sham, 20 Gy) was irradiated. Damage to normal tissues was assessed 84 hours later by histology and blood plasma citrulline levels (gut) and for up to 1 year by non-invasive micro CT imaging (lung). Results The combination treatment of TH-302 with radiotherapy resulted in significant tumor growth delay in OE19 (P = 0.02) and OE21 (P = 0.03) carcinomas, compared to radiotherapy only. Irradiation resulted in a dose-dependent decrease of crypt survival (P

Abdominal cancer patients increasingly undergo multimodality imaging. This study evaluates effects of integrated reading of PET/CT and abdominal MRI on staging outcomes and diagnostic confidence compared to “routine” separate reading. In total, N = 201 patients who underwent abdominal MRI and whole-body F-18 FDG-PET/CT within 14 days were retrospectively analyzed. Original MRI and PET/CT reports were retrieved and reported findings translated into a 5-point confidence score (1 = definitely benign to 5 = definitely malignant) for 7 standardized regions (primary tumor/regional lymph nodes/distant lymph nodes/liver/lung/bone/peritoneum) per patient. Two-reader teams (radiologist + nuclear medicine physician) then performed integrated reading of the images using the same scoring system. Integrated reading led to discrepant findings in 59 of 201 (29%) of patients, with potential clinical impact in 25 of 201 (12%). Equivocal scores decreased from 5.7% (PET/CT) and 5.4% (MRI) to 3.2% (p = 0.05 and p = 0.14). Compared to the original PET/CT reports, integrated reading led to increased diagnostic confidence in 8.9% versus decreased confidence in 6.6% (p = 0.26). Compared with the original MRI reports, an increase in confidence occurred in 9.6% versus a decrease in 6.9% (p = 0.18). The effect on diagnostic confidence was most pronounced in lymph nodes (p = 0.08 vs. MRI), cervical cancer (p = 0.03 vs. MRI), and recurrent disease staging (p = 0.06 vs. PET/CT). Integrated PET/CT+MRI reading alters staging outcomes in a substantial proportion of cases with potential clinical impact in ± 1 out of 9 patients. It can also have a small positive effect on diagnostic confidence, particularly in lymph nodes and cervical cancer, and in post-treatment settings. These findings support further collaboration between radiology and nuclear medicine disciplines. • Increasing numbers of patients undergo multimodality imaging consisting of both MRI and PET/CT for staging of abdominal malignancies. • Integrated reading of FDG-PET/CT and abdominal MR images by a team, consisting of a radiologist and a nuclear medicine physician, can alter staging outcomes compared to separate reporting of the exams in a substantial proportion of cases and with potential clinical impact in ± 1 out of 9 patients. • Integrated PET/CT+MRI reading can have a small positive effect on diagnostic confidence.

Background: DNA methylation signatures describing distinct histological subtypes of oesophageal cancer have been reported. We studied DNA methylation in samples from the MRC OE02 phase III trial, which randomised patients with resectable oesophageal cancer to surgery alone (S) or neoadjuvant chemotherapy followed by surgery (CS).Aim: The aim of the study was to identify epigenetic signatures predictive of chemotherapy benefit in patients with oesophageal adenocarcinoma (OAC) from the OE02 trial and validate the findings in an independent cohort.Methods: DNA methylation was analysed using the Illumina GoldenGate platform on surgically resected OAC specimens from patients in the OE02 trial. Cox proportional hazard analysis was performed to select probes predictive of survival in the CS arm. Non-negative matrix factorisation was used to perform clustering and delineate DNA methylation signatures. The findings were validated in an independent cohort of patients with gastroesophageal adenocarcinoma treated with neoadjuvant chemotherapy.Results: A total of 229 patients with OAC were analysed from the OE02 trial (118 in the CS arm and 111 in the S arm). There was no difference in DNA methylation status between the CS and S arms. A metagene signature was created by dichotomising samples into two clusters. In cluster 1, patients in the CS arm had significant overall survival (OS) benefit (median OS CS: 931 days vs. S: 536 days [HR: 1.54, P = 0.031]). In cluster 2, patients in the CS arm had similar (or worse) OS compared with patients in the S arm (CS: 348 days vs. S: 472 days [HR: 0.70, P = 0.1], and test of interaction was significant (p = 0.005). In the validation cohort (n = 13), there was no difference in DNA methylation status in paired pre- and post-treatment samples. When the epigenetic signature was applied, cluster 1 samples had better OS (median OS, cluster 1: 1174 days vs. cluster 2: 392 days, HR: 3.47, p = 0.059)Conclusions: This is the first and largest study of DNA methylation in patients with OAC uniformly treated in a randomised phase III trial. We identified an epigenetic signature that may serve as a predictive biomarker for chemotherapy benefit in OAC. (C) 2019 Elsevier Ltd. All rights reserved.

International guidelines recommend that prenatal screening for fetal abnormalities should only be offered within a non-directive framework aimed at enabling women in making meaningful reproductive choices. Whilst this position is widely endorsed, developments in cell-free fetal DNA based Non-Invasive Prenatal Testing are now raising questions about its continued suitability for guiding screening policy and practice. This issue is most apparent within debates on the scope of the screening offer. Implied by the aim of enabling meaningful reproductive choices is the idea that screening services should support women in accessing prenatal tests that best enable them to realize the types of reproductive choice that they find important. However, beyond whatever options meet the quality standards required for facilitating an informed decision, the remaining criteria of facilitating autonomous choice is strictly non-directive. As a result, policy makers receive little indication prior to consultation with each individual woman, about what conditions should be prioritized during the offer of screening. In this paper we try to address this issue by using the capabilities approach to further specify the non-directive aim of enabling meaningful reproductive choice. The resulting framework is then used to assess the relative importance of offering prenatal screening where concerning different types of genetic condition. We conclude that greater priority may be ascribed to offering prenatal screening for conditions that more significantly diminish a woman's central capabilities. It follows that serious congenital and earlier-onset conditions are more likely to fulfill these criteria.

Background Metastatic basal cell carcinoma (mBCC) is a very rare entity and diagnosis can be challenging. Therapeutic options are limited and response to targeted therapy is poor. Objective We aimed to demonstrate a clonal relationship between BCCs and their metastases and additionally, to explore which hedgehog pathway related mutations are involved in mBCC. Methods Genetic analysis was conducted in ten primary BCCs and their metastases. Genes relevant for BCC development were analyzed in tumor and metastasis material, either with small molecule molecular inversion probes (smMIPs) for PTCH1, PTCH2, SMO, SUFU, GLI2 and TP53, or with targeted next generation sequencing (tNGS) of the same genes and CDKN2A, CDKN2B, CIC, DAXX, DDX3X, FUBP1, NF1, NF2, PTEN, SETD2, TRAF7, and the TERT promoter. Results In eight of ten patients, identical gene mutations could be demonstrated in the primary tumors and their metastases. A broad spectrum of mutations was found. Four patients had SMO mutations in their tumor and/or metastasis. All SMO mutations found, were known to cause resistance to targeted therapy with vismodegib. Limitations In two patients there was insufficient qualitative DNA available for genetic analysis. Conclusions Molecular testing can help to identify the origin of a BCC metastasis and may be of prognostic and therapeutic value.

Skin cancer can be treated more effectively if the intervention is tailored to the patient's individual needs and the specific characteristics of the tumour. This PhD research found that the most common form of treatment – photodynamic therapy – is only successful in slightly more than half of skin cancer cases compared to a simple cream, which is far more effective. However, modern light therapy remains the preferred treatment for patients over sixty. Doctors should be able to weigh the advantages and disadvantages of a specific treatment method during the diagnosis phase. Making a clearer distinction between individual patients can improve treatment results and lead to a more effective treatment and lower health costs.

Back pain is a common and long-term problem worldwide. In general, the only intervention available is pain control. Although it is not clear why people develop back pain, it is known that spinal cells play an important role in this. Van den Akker developed some unique new models allowing these cells to be examined in more detail. It was shown that the spine contains two different types of cells: a sort of stem cell playing a key role in tissue maintenance and a cell causing damage to spinal tissue in certain circumstances. In the future, these stem cells may be stimulated to repair the affected spinal tissue.

Brachytherapy uses radiation sources in contact with the tumor to eliminate it whilst preserving healthy tissues. This technique has been under continuous development for more than a century now. However, important technical challenges need to be overcome before a definitive clinical implementation of the recently developed technologies can be realized. This study aims to improve treatment accuracy developing tools and studding patient complexities that can lead to better treatment outcome. This research was performed in two countries, Brazil and the Netherlands, in collaboration with hospitals from Sweden and Belgium. It demonstrates an international interest in brachytherapy and its potential applications.

In the Netherlands, one in five people will develop basal cell carcinoma, the most common type of (skin)cancer. Surgical removal is the standard treatment for all variants of basal cell carcinoma. Although non-invasive treatments are available for superficial basal cell carcinomas, these are less effective compared to surgery. By analysing the whole genome, this dissertation demonstrates for the first time that in addition to genetic changes in basal cell carcinomas which were already known, epigenetic changes seem to play an important role as well. Epigenetic changes found in basal cell carcinomas lead to the activation of the immune system. These findings were supported by a study conducted in 124 patients. Treatment with diclofenac 3% gel (a well-known anti-inflammatory drug and painkiller) was shown to be effective by specifically inhibiting signalling pathways active in basal cell carcinomas, among other things. After applying diclofenac 3% gel for eight weeks, more than two-thirds of patients with superficial basal cell carcinoma were tumour-free. This is a first step towards more effective and specific non-invasive treatments. As a result of the involvement of several signalling pathways in basal cell carcinomas, the future lies in combination therapies.

When an ovarian tumour is detected, an ultrasound can help to determine whether that tumour is benign or malignant (cancerous). Unfortunately, current ultrasound-based methods miss over a quarter of all ovarian cancers. As a result, patients are prescribed the wrong treatment. This dissertation examined four new ultrasound methods that are capable of making a more accurate diagnosis than the current method. If the current ultrasound method were to be replaced by one of these methods, ovarian cancer could be diagnosed with greater accuracy. With the right diagnosis, patients receive the right treatment, thereby improving their prognosis.

Endometriosis is a common and benign gynaecological disease. Common symptoms include menstrual pain, pain during intercourse, chronic pain and impaired fertility. This dissertation presents and describes three aspects of endometriosis: genetic and molecular aspects, imaging and quality of life. The B lymphocyte stimulator and the paired-box 2 gene were studied and both appear to play a role in the pathogenesis of endometriosis. This study also investigated the extent to which certain MRI characteristics are associated with the histological infiltration depth in the intestinal wall of patients with colorectal endometriosis. The last chapter of this dissertation explains that symptoms such as chronic pelvic pain and dyspareunia tend to persist in women with endometriosis, despite the patients having been treated in a tertiary hospital. This has a significant impact on their quality of life.

This dissertation reveals the significant disease burden of four sexually transmitted diseases (STD's) – Chlamydia trachomatis, Neisseria gonorrhoeae, Mycoplasma genitalium and Trichomonas vaginalis – for women in rural South Africa. Attention is paid to epidemiological factors, microbiological factors and the clinical treatment of these STD's. The current syndromic treatment strategy for these STD's in South Africa and other low-resource settings generates a limited amount of epidemiological data and leads to both under- and over-treatment of infections. The results of this dissertation stress the importance of extensive surveillance and an improved control strategy, particularly given the increasing levels of antibiotic resistance.

Maastricht University Medical Centre is a specialist centre for the surgical treatment of thymomas and the treatment of the muscular disorder myasthenia gravis (MG). Thymoma removal by means of robotic surgery proved to be a safe and reliable treatment option based on an analysis of all patients who underwent a robotic thymectomy between April 2004 and April 2012. The study also examined the role of robotic thymectomy in the treatment of MG among 125 patients. This form of treatment appeared to be safe, with a low morbidity rate and mortality rate of zero. After a median follow-up study 33 months later, 77% of MG patients had improved neurological function and nearly 33% of patients were in remission. This study also describes the discovery of the human polyomavirus in 39 thymomas.

Background & aims: Malnutrition in head and neck cancer (HNC) patients is associated with increased morbidity and mortality. The purpose of this study is two-fold: to identify the risk of malnutrition in patients with oropharyngeal dysphagia (OD) secondary to HNC, and to determine the relationship between the risk of malnutrition versus tumor characteristics, treatment modality, time interval (between the end of oncological treatment and swallowing assessment date), level of oral intake, body mass index (BMI), aspiration, pharyngeal pooling, and OD-related quality of life (QoL).Methods: The Short Nutritional Assessment Questionnaire (SNAQ) was used to screen patients for the risk of malnutrition. Patients underwent a standardized swallowing examination protocol including an endoscopic evaluation of swallowing.Results: Seventy-five dysphagic HNC patients were included. Forty-eight percent of the patients presented a high risk of malnutrition using SNAQ. The majority of the patients (81.3%) was on a total oral diet. Moreover, BMI did not appear to be a reliable measure to screen for malnutrition as a normal BMI was often associated with an increased risk of malnutrition on the SNAQ. In contrast, patients who were underweight or overweight did not show an association with a high risk of malnutrition. With the exception of BMI, no other patient and tumor characteristics were found to be associated with the risk of malnutrition.Conclusions: This study emphasizes the importance of early nutritional screening in dysphagic HNC patients, as almost half of these patients presented a high risk of malnutrition. Malnutrition screening using SNAQ can identify HNC patients with OD who are at risk of malnutrition and subsequently need to be referred to a dietician for additional nutritional assessment, diagnosis of malnutrition, and nutritional support, even when their BMI is within normal range. (C) 2021 The Author(s). Published by Elsevier Ltd on behalf of European Society for Clinical Nutrition and Metabolism.

Introduction Stage IV large cell neuroendocrine carcinoma (LCNEC) of the lung generally presents as disseminated and aggressive disease with a Ki-67 proliferation index (PI) 40–80%. LCNEC can be subdivided in two main subtypes: the first harboring TP53/RB1 mutations (small-cell lung carcinoma (SCLC)-like), the second with mutations in TP53 and STK11/KEAP1 (non-small-cell lung carcinoma (NSCLC)-like). Here we evaluated 11 LCNEC patients with only a solitary brain metastasis and evaluate phenotype, genotype and follow-up. Methods Eleven LCNEC patients with solitary brain metastases were analyzed. Clinical characteristics and survival data were retrieved from medical records. Pathological analysis included histomorphological analysis, immunohistochemistry (pRB and Ki-67 PI) and next-generation sequencing (TP53, RB1, STK11, KEAP1 and MEN1). Results All patients had N0 or N1 disease. Median overall survival (OS) was 12 months (95% confidence interval (CI) 5.5–18.5 months). Mean Ki-67 PI was 59% (range 15–100%). In 6/11 LCNEC Ki-67 PI was ≤40%. OS was longer for Ki-67 ≤40% compared to >40% (17 months (95% CI 11–23 months) vs 5 months (95% CI 0.7–9 months), P = 0.007). Two patients were still alive at follow-up after 86 and 103 months, both had Ki-67 ≤40%. 8/11 patients could be subclassified, and both SCLC-like (n = 6) and NSCLC-like (n = 2) subtypes were present. No MEN1 mutation was found. Conclusion Stage IV LCNEC with a solitary brain metastasis and N0/N1 disease show in the majority of cases Ki-67 PI ≤40% and prolonged survival, distinguishing them from general LCNEC. This unique subgroup can be both of the SCLC-like and NSCLC-like subtype.

Atlas-based automatic segmentation is used in radiotherapy planning to accelerate the delineation of organs at risk (OARs). Atlas selection has been proposed as a way to improve the accuracy and execution time of segmentation, assuming that, the more similar the atlas is to the patient, the better the results will be. This paper presents an analysis of atlas selection methods in the context of radiotherapy treatment planning. For a range of commonly contoured OARs, a thorough comparison of a large class of typical atlas selection methods has been performed. For this evaluation, clinically contoured CT images of the head and neck ( ${N}={316}$ ) and thorax ( ${N}={280}$ ) were used. The state-of-the-art intensity and deformation similarity-based atlas selection methods were found to compare poorly to perfect atlas selection. Counter-intuitively, atlas selection methods based on a fixed set of representative atlases outperformed atlas selection methods based on the patient image. This study suggests that atlas-based segmentation with currently available selection methods compares poorly to the potential best performance, hampering the clinical utility of atlas-based segmentation. Effective atlas selection remains an open challenge in atlas-based segmentation for radiotherapy planning.

Introduction: To study the association between placental pathology and neonatal birthweight and outcomes, and whether a combination of first trimester biomarkers and fetal growth velocity can predict placental lesions.Methods: The presence of maternal vascular malperfusion (MVM) lesions (Amsterdam criteria) was recorded in a retrospective cohort of singleton pregnancies in the Maastricht University Medical Centre, 2011-2018. First trimester maternal characteristics and PAPP-A, PlGF and sFlt-1 levels were collected. Fetal growth velocities were calculated (mm/week) from 20 to 32 weeks for abdominal circumference, biparietal diameter, head circumference and femur length. Data were compared between neonates with 'small for gestational age' (SGA p50 (reference), using one-way ANOVA and post hoc test.Results: There were significantly more MVM lesions in the SGA group (94.6% p Discussion: Placental MVM lesions correlated inversely with birthweight even in AGA neonates, and was associated with slower fetal growth and more adverse outcome in SGA neonates. A combination of first trimester biomarkers and fetal growth velocity had good prediction of placental MVM lesions, as an indicator of fetal growth restriction irrespective of neonatal weight.

Highlights • Typically encountered CT exposure variations result in radiomics values distortion. • Proposed correction method suppresses the non-tumor related variation in radiomics. • The clinical relevance was shown using a 221 lung cancer patient cohort., Purpose Radiomics are quantitative features extracted from medical images. Many radiomic features depend not only on tumor properties, but also on non-tumor related factors such as scanner signal-to-noise ratio (SNR), reconstruction kernel and other image acquisition settings. This causes undesirable value variations in the features and reduces the performance of prediction models. In this paper, we investigate whether we can use phantom measurements to characterize and correct for the scanner SNR dependence. Methods We used a phantom with 17 regions of interest (ROI) to investigate the influence of different SNR values. CT scans were acquired with 9 different exposure settings. We developed an additive correction model to reduce scanner SNR influence. Results Sixty-two of 92 radiomic features showed high variance due to the scanner SNR. Of these 62 features, 47 showed at least a factor 2 significant standard deviation reduction by using the additive correction model. We assessed the clinical relevance of radiomics instability by using a 221 NSCLC patient cohort measured with the same scanner. Conclusions Phantom measurements show that roughly two third of the radiomic features depend on the exposure setting of the scanner. The dependence can be modeled and corrected significantly reducing the variation in feature values with at least a factor of 2. More complex models will likely increase the correctability. Scanner SNR correction will result in more reliable radiomics predictions in NSCLC.

BACKGROUND Incidence trends of nonmelanoma skin cancer show an increase. Few data have been published about the incidence of Bowen disease (BD). Three previous studies, conducted more than 15 years ago in North America, found large variation in incidence rates in Caucasians, and trends over longer periods have never been studied.OBJECTIVE To estimate the incidence of BD in a Caucasian population in Northern Europe (Maastricht, the Netherlands) between 2003 and 2013.METHODS Primary and histologically confirmed BD, diagnosed in Maastricht, the Netherlands, in the years 2003, 2008, and 2013, was retrieved from a pathology database. Age-standardized and sex-specific incidence rates per 100,000 inhabitants were calculated by using the age distribution of the European standard population of 2013.RESULTS A statistically significant increase in the annual age-standardized incidence rates per 100,000 people was found from 8.1 (95% confidence interval [CI] 3.7-12.5) in 2003 to 68.9 (95% CI 57.2-80.7) in 2013 (p CONCLUSION These findings suggest an increase in the annual age-standardized incidence rates in BD.

Purpose Radiomics is the process to automate tumor feature extraction from medical images. This has shown potential for quantifying the tumor phenotype and predicting treatment response. The three major challenges of radiomics research and clinical adoption are: (a) lack of standardized methodology for radiomics analyses, (b) lack of a universal lexicon to denote features that are semantically equivalent, and (c) lists of feature values alone do not sufficiently capture the details of feature extraction that might nonetheless strongly affect feature values (e.g. image normalization or interpolation parameters). These barriers hamper multicenter validation studies applying subtly different imaging protocols, preprocessing steps and radiomics software. We propose an open‐source ontology‐guided radiomics analysis workflow (O‐RAW) to address the above challenges in the following manner: (a) distributing a free and open‐source software package for radiomics analysis, (b) deploying a standard lexicon to uniquely describe features in common usage and (c) provide methods to publish radiomic features as a semantically interoperable data graph object complying to FAIR (findable accessible interoperable reusable) data principles. Methods O‐RAW was developed in Python, and has three major modules using open‐source component libraries (PyRadiomics Extension and PyRadiomics). First, PyRadiomics Extension takes standard DICOM‐RT (Radiotherapy) input objects (i.e. a DICOM series and an RTSTRUCT file) and parses them as arrays of voxel intensities and a binary mask corresponding to a volume of interest (VOI). Next, these arrays are passed into PyRadiomics, which performs the feature extraction procedure and returns a Python dictionary object. Lastly, PyRadiomics Extension parses this dictionary as a W3C‐compliant Semantic Web “triple store” (i.e., list of subject‐predicate‐object statements) with relevant semantic meta‐labels drawn from the radiation oncology ontology and radiomics ontology. The output can be published on an SPARQL endpoint, and can be remotely examined via SPARQL queries or to a comma separated file for further analysis. Results We showed that O‐RAW executed efficiently on four datasets with different modalities, RIDER (CT), MMD (CT), CROSS (PET) and THUNDER (MR). The test was performed on an HP laptop running Windows 7 operating system and 8GB RAM on which we noted execution time including DICOM images and associated RTSTRUCT matching, binary mask conversion of a single VOI, batch‐processing of feature extraction (105 basic features in PyRadiomics), and the conversion to an resource description framework (RDF) object. The results were (RIDER) 407.3, (MMD) 123.5, (CROSS) 513.2 and (THUNDER) 128.9 s for a single VOI. In addition, we demonstrated a use case, taking images from a public repository and publishing the radiomics results as FAIR data in this study on http://www.radiomics.org. Finally, we provided a practical instance to show how a user could query radiomic features and track the calculation details based on the RDF graph object created by O‐RAW via a simple SPARQL query. Conclusions We implemented O‐RAW for FAIR radiomics analysis, and successfully published radiomic features from DICOM‐RT objects as semantic web triples. Its practicability and flexibility can greatly increase the development of radiomics research and ease transfer to clinical practice.

AIM: To evaluate the diagnostic performance of diffusion-weighted imaging (DWI), with and without fusion images, in addition to regular T2-weighted (T2W) sequences for assessment of parametrial invasion.MATERIALS AND METHODS: This prospective cohort included cervical cancer patients who underwent preoperative magnetic resonance imaging (MRI) with T2W and axial DWI sequences prior to radical hysterectomy. Retrospectively, two radiologists independently and blindly scored the likelihood of parametrial invasion by means of a six-point confidence scale. Parametrial invasion was determined by surgical-pathological results. Performance indices for diagnostic tests and area under the receiver operating characteristic curve (AUC) analyses were performed. P-Values ofRESULTS: Of 65 included patients, parametrial invasion was found in eight patients. A statistically significant increase in diagnostic performance for the assessment of parametrial invasion was found when T2W MRI was fused with DWI (fusion T2W/DWI), especially decreasing false-positive findings: the positive predictive value of parametrial invasion using T2W MRI versus fusion T2W MRI/DWI increased from 29% to 50% for observer 1 and from 23% to 50% for observer 2 (AUC=0.80-0.67 versus 0.94-0.94).CONCLUSIONS: Fusion T2W MRI/DWI shows a significant increase in diagnostic performance for the assessment of parametrial invasion in early-stage cervical carcinoma. (C) 2019 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.

Prediction modelling with radiomics is a rapidly developing research topic that requires access to vast amounts of imaging data. Methods that work on decentralized data are urgently needed, because of concerns about patient privacy. Previously published computed tomography medical image sets with gross tumour volume (GTV) outlines for non-small cell lung cancer have been updated with extended follow-up. In a previous study, these were referred to as Lung1 (n = 421) and Lung2 (n = 221). The Lung1 dataset is made publicly accessible via The Cancer Imaging Archive (TCIA; https://www.cancerimagingarchive.net). We performed a decentralized multi-centre study to develop a radiomic signature (hereafter “ZS2019”) in one institution and validated the performance in an independent institution, without the need for data exchange and compared this to an analysis where all data was centralized. The performance of ZS2019 for 2-year overall survival validated in distributed radiomics was not statistically different from the centralized validation (AUC 0.61 vs 0.61; p = 0.52). Although slightly different in terms of data and methods, no statistically significant difference in performance was observed between the new signature and previous work (c-index 0.58 vs 0.65; p = 0.37). Our objective was not the development of a new signature with the best performance, but to suggest an approach for distributed radiomics. Therefore, we used a similar method as an earlier study. We foresee that the Lung1 dataset can be further re-used for testing radiomic models and investigating feature reproducibility.

Purpose: To study the number of disruptions in patient processes in a radiotherapy centre after the replacement of an Electronic Health Record (EHR), integrating information tools for patient care and billing.Methods: Our self-made Electronic Medical Record was replaced by a new EHR, including clinical path and workflow-management. A social-technological approach was used to reduce complexity. We measured disruptions in patient processes by the number and type of EHR related root causes and EHR-related incidents that reached patients, in our patient safety system 12 months before implementing the new EHR, 6 months after implementation (transition period) and 24 months after the transition period. We used Mann-Whitney U and X-2 tests to compare data before and after implementation.Results: An increase of disruptions occurred only temporarily during 6 months. After this period, the number stabilized to the level before implementation while having more functionalities and benefits. Neither the number nor the severity of incidents reaching patients increased.Conclusions: Disruptions in patient processes are considered as a main barrier for implementing an EHR. Using a social/technical approach, the increase in disruptions did only temporarily occur and did not reach patients. We think it is important to share this insight with physicians because literature shows that their long-term opinion regarding the usefulness of the EHR is often based on the experience in the first months after implementation. Management of expectations is recommended.Advances in knowledge: This study is the first of its kind measuring long-term effects of EHR on patient processes in radiotherapy.

Background Detecting pathological breast calcifications remains challenging. Based on recent studies, contrast-enhanced spectral mammography (CESM) was shown to be superior compared to full-field digital mammography (FFDM). Purpose To evaluate the diagnostic accuracy of CESM in suspicious breast calcifications and its impact on surgical decision-making. Material and Methods All screening recalled patients with suspicious calcifications that underwent CESM in the period October 2012 until September 2015 were included. One experienced radiologist provided a BI-RADS classification for the FFDM images only. The evaluation was repeated for the CESM exam. In a simulated tumor board meeting, two breast surgeons decided on the preferred surgical treatment (breast conservation therapy [BCT] versus mastectomy) for all malignant cases. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were calculated defining BI-RADS >= 4 as being malignant. In addition, differences in surgical decision-making were analyzed and compared using McNemar's test. Results In total, 147 women were included in this study (mean age = 61 years; age range = 49-75 years). Pathology showed 82 benign and 65 malignant lesions, of which 33 were ductal carcinomas in situ and 32 were invasive lesions. Diagnostic performances of CESM (differences compared to FFDM in brackets) were: sensitivity 93.8% (+3%), specificity 36.6% (-2.5%), PPV 54% (0%), and NPV 88.2% (+4%). Based on low-energy images, surgeons suggested BCT in 89% of the cases. Based on the CESM exam, no statistical changes in decisions were observed (86% BCT, P = 0.453). Conclusion CESM only slightly improves the diagnostic accuracy of the evaluation of breast calcifications. It is not of added value compared to FFDM in guiding surgical decision-making.

Peptide receptor radionuclide therapy (PRRT) is an effective treatment for patients with neuroendocrine neoplasms. The aim of this study was to identify clinical and treatment parameters associated with progression-free survival (PFS) and overall survival (OS). Methods: All patients treated from October 2002 until March 2016 at the Zentralklinik Bad Berka with at least 3 administrations of PRRT (maximal interval of 6 mo between consecutive administrations) were included. Data were collected in 5 categories: general patient characteristics, tumor characteristics, prior treatments, radioisotope used for PRRT, and blood chemistry. Survival was analyzed using Kaplan-Meier curves. Univariate and multivariate Cox regression analyses were performed to identify parameters associated with PFS and OS. Results: In total, 782 patients were included, with a median follow-up of 36 mo. The median PFS and OS were 22 and 53 mo, respectively. Parameters associated with lower PFS in the multivariate analysis were a Ki-67 of more than 5%, previous treatment with interferon-alpha and chemotherapy, presence of diabetes, and chromogranin-A (CgA) levels higher than 336 mu g/L. Parameters associated with lower OS were a Ki-67 of more than 10%, performance status of at least 1, previous chemotherapy and ablation, and CgA levels higher than 112 mu g/L. Conclusion: Higher Ki-67 values, as well as higher CgA levels and previous chemotherapy, had a negative outcome on both PFS and OS. Furthermore, PFS was negatively associated with previous interferon-alpha treatment and diabetes, whereas lower OS was related to prior ablation and higher performance status.

Background: Prostate cancer and urinary bladder cancer are frequently occurring cancers with few risk factors identified. We examined the relation of Mediterranean diet (MD) adherence with risks of prostate and bladder cancer in the Netherlands Cohort Study (NLCS). Methods: Data were available for 58,279 men and 62,573 women, who completed a baseline questionnaire on diet and other cancer risk factors. Multiple MD scores, including the alternate Mediterranean diet score without alcohol (aMEDr), were calculated to assess MD adherence. After 20.3 years of follow-up, 3,868 prostate cancer cases (advanced: 1,256) and 1,884 bladder cancer cases could be included in multivariable Cox proportional hazards analyses. Results: aMEDr was not associated with advanced prostate cancer risk [hazard ratio (HR)per 2-point increment (95% confidence interval, 95% CI) = 1.06 (0.96–1.17)]. In contrast, higher aMEDr values were associated with a significantly increased risk of nonadvanced prostate cancer (Ptrend = 0.04). For bladder cancer risk, no association was observed with aMEDr [HRper 2-point increment (95% CI) = 1.00 (0.92–1.09)]. Absolute scores based on the World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) dietary recommendations were not associated with prostate or bladder cancer risk. Conclusions: MD adherence, measured by aMEDr or other MD scores, was not associated with decreased risks of advanced prostate cancer and bladder cancer in the NLCS. Higher levels of care-seeking behavior, screening attendance, and prostate cancer awareness in higher educated men with healthier lifestyles could potentially explain the positive associations observed for nonadvanced prostate cancer risk. Impact: MD adherence does not seem to reduce the risk of (advanced) prostate cancer or bladder cancer.

Radiation-induced lung injury to normal airway epithelium is a frequent side-effect and dose-limiting factor in radiotherapy of tumors in the thoracic cavity. NOTCH signaling plays key roles in self-renewal and differentiation of upper airway basal lung stem cells during development, and the NOTCH pathway is frequently deregulated in lung cancer. In preclinical lung cancer models, NOTCH inhibition was shown to improve the radiotherapy response by targeting tumor stem cells, but the effects in combination with irradiation on normal lung stem cells are unknown. NOTCH/γ-secretase inhibitors are potent clinical candidates to block NOTCH function in tumors, but their clinical implementation has been hampered by normal tissue side-effects. Here we show that NOTCH signaling is active in primary human- and murine-derived airway epithelial stem cell models and when combined with radiation NOTCH inhibition provokes a decrease in S-phase and increase in G1-phase arrest. We show that NOTCH inhibition in irradiated lung basal stem cells leads to a more potent activation of the DNA damage checkpoint kinases pATM and pCHK2 and results in an increased level of residual 53BP1 foci in irradiated lung basal stem cells reducing their capacity for self-renewal. The effects are recapitulated in ex vivo cultured lung basal stem cells after in vivo whole thorax irradiation and NOTCH inhibition. These results highlight the importance of studying normal tissue effects that may counteract the therapeutic benefit in the use of NOTCH/γ-secretase inhibitors in combination with radiation for antitumor treatment.

Background The development of high throughput sequencing techniques provides us with the possibilities to obtain large data sets, which capture the effect of dynamic perturbations on cellular processes. However, because of the dynamic nature of these processes, the analysis of the results is challenging. Therefore, there is a great need for bioinformatics tools that address this problem. Results Here we present DynOVis, a network visualization tool that can capture dynamic dose-over-time effects in biological networks. DynOVis is an integrated work frame of R packages and JavaScript libraries and offers a force-directed graph network style, involving multiple network analysis methods such as degree threshold, but more importantly, it allows for node expression animations as well as a frame-by-frame view of the dynamic exposure. Valuable biological information can be highlighted on the nodes in the network, by the integration of various databases within DynOVis. This information includes pathway-to-gene associations from ConsensusPathDB, disease-to-gene associations from the Comparative Toxicogenomics databases, as well as Entrez gene ID, gene symbol, gene synonyms and gene type from the NCBI database. Conclusions DynOVis could be a useful tool to analyse biological networks which have a dynamic nature. It can visualize the dynamic perturbations in biological networks and allows the user to investigate the changes over time. The integrated data from various online databases makes it easy to identify the biological relevance of nodes in the network. With DynOVis we offer a service that is easy to use and does not require any bioinformatics skills to visualize a network.

Objective To construct a mediastinal-specific fluorine-18-fluorodeoxyglucose (F-18-FDG)-PET/MR protocol with high-quality MRI of minimal acquisition-time and comparable diagnostic value to F-18-FDG-PET/computed tomography (CT).Materials and methods Fifteen healthy participants received PET/MRI and 10 patients with mediastinal tumours (eight non-small-cell lung, two oesophageal cancer) received F-18-FDG-PET/MRI immediately after F-18-FDG-PET/CT. Sequences volume interpolated breath-hold examination (T1-VIBE) and Half-Fourier acquisition single-shot turbo spin echo (T2-HASTE) were optimised by varying the parameters: breath-hold (BH, end-expiration), fat suppression (spectral adiabatic inversion recovery), and ECG-triggering (ECG, end-diastole). Image quality (IQ) of each sequence-variation was qualitatively scored by medical experts and quantitatively assessed by calculating signal-to-noise ratios, contrast relative to muscle, standardized-uptake-value, and tumour-to-blood ratios. Patient comfort was evaluated on patients' experience. Diagnostic accuracy of F-18-FDG-PET/MRI was compared to F-18-FDG-PET/CT, in reference to histopathology/cytopathology.Results ECG-triggered T1-VIBE images showed the highest signal-to-noise ratio (P 0.9). Qualitative IQ of T1-VIBE and T2-HASTE declined after spectral adiabatic inversion recovery fat-suppression. All patients could maintain BH at end-expiration and reported no discomfort. Diagnostic performance of F-18-FDG-PET/MR was not significantly different from F-18-FDG-PET/CT with comparable staging, standardized-uptake-values, and tumour-to-blood ratios. However, T-status was more often over-staged on F-18-FDG-PET/CT, while N-status was more frequently under-staged on F-18-FDG-PET/MR.Conclusion ECG-triggered T1-VIBE sequences acquired during short, multiple BHs are recommended for mediastinal imaging using F-18-FDG-PET/MR. With dedicated protocols, F-18-FDG-PET/MRI will be useful in thoracic oncology and aid in diagnostic evaluation and tailored treatment decision-making. Copyright (C) 2019 Wolters Kluwer Health, Inc. All rights reserved.

Introduction: Leptomeningeal metastases (LMs) are associated with dismal prognosis in NSCLC. Optimal management remains unknown in patients with EGFR-mutated NSCLC after initial tyrosine kinase inhibitor (TKI) failure.Methods: We conducted a multicenter retrospective study including patients with EGFR-mutated NSCLC and LM. TKI failure was defined as diagnosis of LM on TKI, or progression of known LM on TKI.Results: Ninety-two patients were included, median age of 60 years, predominantly female (68%), never-smokers (74%). EGFR mutations included L858R (45%), exon 19 deletions (28%), or other mutations (14%). Median time to LM diagnosis was 18.5 months after initial diagnosis of advanced NSCLC. LM was diagnosed after a median of 2 (range: 0-9) systemic therapies. Median overall survival from LM diagnosis was 6.1 months (95% confidence interval [ CI]: 4.2-7.6 months). Among 87 patients with TKI failure, patients rechallenged with TKI (n = 50) had a median LM overall survival of 7.6 months (95% CI: 5.7-10.9) compared to 4.2 months (95% CI: 1.6-6.7) in patients without further therapy. Overall, 60% of patients rechallenged with TKI experienced clinical benefit (clinical response or stable disease >2 months), and 23% were treatment failure-free at 6 months. Clinical benefit was reported in 11 of 20 (55%) patients treated with erlotinib after afatinib or gefitinib. Strategies based on increasing dose intensity (n = 17) yielded clinical benefit in 59% of patients. All four patients who received osimertinib after first-and second-generation TKI experienced clinical benefit.Conclusions: TKI rechallenge strategies, including dosing intensification, may improve clinical outcomes of patients with LM from EGFR-mutated NSCLC after initial TKI failure. (C) 2019 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

Background: Lymphedema is a chronic, progressive disease consisting of tissue swelling resulting from excessive retention of lymphatic fluid. Measuring upper limb volume is crucial in patients to detect disease progression and to study the effects of treatment. The aim is to assess the validity and reliability of a newly developed system, Peracutus Aqua Meth, for measuring the upper limb volume compared with the gold standard water volumetry device. (In this study, the Bravometer was used). Methods and Results: Healthy volunteers were recruited in October 2017. Three measurements were performed per device. The obtained data were recorded per measurement, device, and researcher. Primary outcome was to determine the validity and reliability of the Peracutus Aqua Meth. Secondary outcomes were intra- and interrater reliability, measurement time, self-reported participant satisfaction, and influence of body mass index (BMI). Thirty-nine healthy volunteers were included. Mean differences in the validity in the Peracutus Aqua Meth and Bravometer were 47.26 and 78.16 mL, respectively (p = 0.04), with a Pearson's r of 0.99. Intra- and interrater reliability of the Peracutus Aqua Meth were both 0.99, in the Bravometer 0.96 and 0.97, respectively (p

Background. Residual axillary lymph node involvement after neoadjuvant systemic therapy (NST) is the determining factor for postmastectomy radiation therapy (PMRT). Preoperative identification of patients needing PMRT is essential to enable shared decision-making when choosing the optimal timing of breast reconstruction. We determined the risk of positive sentinel lymph node (SLN) after NST in clinically node-negative (cN0) breast cancer.Methods. All cT1-3N0 patients treated with NST followed by mastectomy and SLNB between 2010 and 2016 were identified from the Netherlands Cancer Registry. Rate of positive SLN for different breast cancer subtypes was determined. Logistic regression analysis was performed to determine correlated clinicopathological variables with positive SLN.Results. In total 788 patients were included, of whom 25.0% (197/788) had positive SLN. cT1-3N0 ER+HER2+, cT1-3N0 ER-HER2+, and cT1-2N0 triple-negative patients had the lowest rate of positive SLN: 7.2-11.5%, 0-6.3%, and 2.9-6.2%, respectively. cT1-3N0 ER+HER2- and cT3N0 triple-negative patients had the highest rate of positive SLN: 23.8-41.7% and 30.4%, respectively. Multivariable regression analysis showed that cT2 (odds ratio [OR] 1.93; 95% confidence interval [CI] 1.01-3.96), cT3 (OR 2.56; 95% CI 1.30-5.38), grade 3 (OR 0.44; 95% CI 0.21-0.91), and ER+HER2- subtype (OR 3.94; 95% CI 1.77-8.74) were correlated with positive SLN.Conclusions. In cT1-3N0 ER+HER2+, cT1-3N0 ER-HER2+, and cT1-2N0 triple-negative patients treated with NST, immediate reconstruction can be considered an acceptable option due to low risk of positive SLN. In cT1-3N0 ER+HER2- and cT3N0 triple-negative patients treated with NST, risks and benefits of immediate reconstruction should be discussed with patients due to the relatively high risk of positive SLN.

PURPOSE: The Bravos afterloader system was released by Varian Medical Systems in October of 2018 for high-dose-rate brachytherapy with Ir-192 sources, containing new features such as the CamScale (a new device for daily quality assurance and system recalibration), channel length verification, and different settings for rigid and flexible applicators. This study mechanically evaluated the Bravos system precision and accuracy for clinically relevant scenarios, using dummy sources.METHODS AND MATERIALS: The system was evaluated after three sets of experiments: (1) The CamScale was used to verify inter- and infra-channel dwelling variability and system calibration; (2) A high-speed camera was used to verify the source simulation cable movement inside a transparent quality assurance device, where dwell positions, dwell times, transit times, speed profiles, and accelerations were measured; (3) The source movement inside clinical applicators was captured with an imaging panel while being exposed to an external kV source. Measured and planned dwell positions and times were compared.RESULTS: Maximum deviations between planned and measured dwell positions and times for the source cable were 0.4 mm for the CamScale measurements and 0.07 seconds for the high-speed camera measurements. Mean dwell position deviations inside clinical applicators were below 1.2 mm for all applicators except the ring that required an offset correction of 1 mm to achieve a mean deviation of 0.4 mm.CONCLUSIONS: Features of the Bravos afterloader system provide a robust and precise treatment delivery. All measurements were within manufacturer specifications. (C) 2019 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive cancer arising from T-cell progenitors. Although current treatments, including chemotherapy and glucocorticoids, have significantly improved survival, T-ALL remains a fatal disease and new treatment options are needed. Since more than 60% of T-ALL cases bear oncogenic NOTCH1 mutations, small molecule inhibitors of NOTCH1 signalling; gamma-secretase inhibitors (GSI), are being actively investigated for the treatment of T-ALL. Unfortunately, GSI have shown limited clinical efficacy and dose-limiting toxicities. We hypothesized that by combining known drugs, blocking NOTCH activity through another mechanism, may synergize with GSI enabling equal efficacy at a lower concentration. Here, we show that the clinically used anti-malarial drug chloroquine (CQ), an inhibitor of lysosomal function and autophagy, decreases T-ALL cell viability and proliferation. This effect of CQ was not observed in GSI-resistant T-ALL cell lines. Mechanistically, CQ impairs the redox balance, induces ds DNA breaks and activates the DNA damage response. CQ also interferes with intracellular trafficking and processing of oncogenic NOTCH1. Interestingly, we show for the first time that the addition of CQ to gamma-secretase inhibition has a synergistic therapeutic effect on T-ALL and reduces the concentration of GSI required to obtain a reduction in cell viability and a block of proliferation. Overall, our results suggest that CQ may be a promising repurposed drug in the treatment of T-ALL, as a single treatment or in combination with GSI, increasing the therapeutic ratio.

European journal of nuclear medicine and molecular imaging 46(7), 1428-1438 (2019). doi:10.1007/s00259-019-04292-w, Published by Springer-Verl., Heidelberg [u.a.]

EssentialsBleeding in chemotherapy induced thrombocytopenia (CIT) might be influenced by hyperfibrinolysis. t-PA-thromboelastography is a fast and reliable assay for hyperfibrinolysis in CIT patients. Clots of CIT patients are more susceptible to t-PA induced lysis compared to healthy individuals. Besides platelets, other factors are likely to influence clot lysis in CIT patients. Background Bleeding events in chemotherapy-induced thrombocytopenic (CIT) patients with similar platelet counts might be influenced by changes in clot lysis potential. Objectives To investigate, in an observational study, thromboelastographic lysis parameters, alterations in clot strength and susceptibility to clot lysis in CIT patients. To identify factors associated with fibrinolytic profiles, and to evaluate the effects of platelet transfusions. Methods Independent determinants of tissue-type plasminogen activator (t-PA)-ROTEM lysis parameters were identified with multivariable linear regression. Clot formation, strength and lysis parameters were compared with the results of healthy individuals. Characteristics of CIT patients with and without hyperfibrinolytic profiles were compared. t-PA-ROTEM results before, 1 hour after and 24 hours after platelet transfusion were compared. Results A total of 72 consecutive CIT patients were included. t-PA-ROTEM lysis parameters correlated with changes in fibrinolytic proteins. Clot formation time was longer, maximum clot firmness was weaker and lysis times were shorter than in healthy individuals. CIT patients had low plasminogen activator inhibitor-1 and thrombin-activatable fibrinolysis inhibitor levels, and 40% showed hyperfibrinolytic profiles. Platelet transfusions resulted in less hyperfibrinolytic profiles in many, but not all CIT patients. Patients without hyperfibrinolytic profiles had higher fibrinogen, factor VIII and alpha(2)-antiplasmin levels. Conclusions t-PA-ROTEM can be used as a fast and reliable assay to detect hyperfibrinolytic profiles in CIT patients. CIT patients have weaker clots, which are more susceptible to clot lysis, than healthy individuals. Besides platelets, other factors are likely to influence clot susceptibility to fibrinolysis in CIT patients. The impact of a hyperfibrinolytic t-PA-ROTEM profile on bleeding remains to be investigated.

Background Mediterranean diet (MD) adherence has been associated with reduced risks of esophageal and gastric cancer (subtypes) in a limited number of studies. We prospectively investigated associations between MD adherence and risks of esophageal squamous cell carcinoma (ESCC), esophageal adenocarcinoma (EAC), gastric cardia adenocarcinoma (GCA), and gastric non-cardia adenocarcinoma (GNCA) in a Dutch cohort. Methods Analyses were conducted using data from the 120852 participants of the Netherlands Cohort Study (NLCS), who were aged between 55 and 69 years at enrollment. Various MD scores, with and without alcohol, were calculated to estimate MD adherence. Using 20.3 years of follow-up, 133 ESCC, 200 EAC, 191 GCA, and 586 GNCA cases could be included in multivariable Cox regression analyses. Results Of the investigated scores, the alternate Mediterranean diet score without alcohol (aMEDr) performed best. aMEDr was inversely associated with risks of GCA and GNCA in men and women. However, statistical significance was only reached in men [ptrend: 0.019 (GCA), 0.016 (GNCA)]. Furthermore, higher aMEDr values were significantly associated with a reduced ESCC risk in men [HRper two−point increment (95% CI) = 0.57 (0.41–0.80), ptrend = 0.013], but not in women (pheterogeneity = 0.008). There was no evidence of an association between aMEDr and EAC risk. Educational level was a significant effect modifier for the association between aMEDr and GNCA risk (pheterogeneity = 0.0073). Conclusions Higher MD adherence was associated with reduced risks of ESCC, GCA, and GNCA in the NLCS. However, the decreased ESCC risk might be limited to men. Electronic supplementary material The online version of this article (10.1007/s10120-019-00927-x) contains supplementary material, which is available to authorized users.