Effect of a FIT-Based Colorectal Cancer Screening Program on Mortality Estimated by the Regression Discontinuity Design.

The fecal immunochemical test (FIT) has been implemented in colorectal cancer (CRC) screening programs, but effect evaluations are lacking. We evaluated the effect of a positive FIT on all-cause and CRC mortality using the regression discontinuity design. The Danish CRC screening program invites all residents 50-74 years old, using a 20-µg hemoglobin/g feces cutoff for colonoscopy referral. In this cohort study, we followed all first-time screening participants from 2014-2019 until 2020. We estimated the local effect of screening results, of just above the cutoff vs. just below, as hazard ratios (HRs) between models fitted at each side of the cutoff. We conducted the analysis within a narrow hemoglobin range (≥17 and <23, n = 16,428) and a wider range (≥14 and <26, n = 35,353). Those screened just above the cutoff had lower all-cause mortality compared with below (HR = 0.87, 95% confidence interval: 0.69; 1.10), estimated from the narrow range. The CRC mortality analysis had few outcomes. In the wider range, those with a FIT just above the cutoff had a lower hazard of CRC mortality compared with just below the cutoff (HR = 0.49, 95% confidence interval: 0.17; 1.41). A FIT result just above the cutoff, leading to referral to colonoscopy, pointed towards reduced all-cause and CRC mortality compared with just below the cutoff.

Impact of multimorbidity and polypharmacy on mortality after cancer: a nationwide registry-based cohort study in Denmark 2005-2017.

BACKGROUND: Concurrent chronic diseases and treatment hereof in patients with cancer may increase mortality. In this population-based study we examined the individual and combined impact of multimorbidity and polypharmacy on mortality, across 20 cancers and with 13-years follow-up in Denmark. MATERIALS AND METHODS: This nationwide study included all Danish residents with a first primary cancer diagnosed between 1 January 2005 and 31 December 2015, and followed until the end of 2017. We defined multimorbidity as having one or more of 20 chronic conditions in addition to cancer, registered in the five years preceding diagnosis, and polypharmacy as five or more redeemed medications 2-12 months prior to cancer diagnosis. Cox regression analyses were used to estimate the effects of multimorbidity and polypharmacy, as well as the combined effect on mortality. RESULTS: A total of 261,745 cancer patients were included. We found that patients diagnosed with breast, prostate, colon, rectal, oropharynx, bladder, uterine and cervical cancer, malignant melanoma, Non-Hodgkin lymphoma, and leukemia had higher mortality when the cancer diagnosis was accompanied by multimorbidity and polypharmacy, while in patients with cancer of the lung, esophagus, stomach, liver, pancreas, kidney, ovarian and brain & central nervous system, these factors had less impact on mortality. CONCLUSION: We found that multimorbidity and polypharmacy was associated with higher mortality in patients diagnosed with cancer types that typically have a favorable prognosis compared with patients without multimorbidity and polypharmacy. Multimorbidity and polypharmacy had less impact on mortality in cancers that typically have a poor prognosis.

Harnessing the Value of Tripolium pannonicum and Crithmum maritimum Halophyte Biomass through Integrated Green Biorefinery.

Bioactive extracts are often the target fractions in bioprospecting, and halophyte plants could provide a potential source of feedstock for high-value applications as a part of integrated biorefineries. Tripolium pannonicum (Jacq.) Dobrocz. (sea aster) and Crithmum maritimum L. (sea fennel) are edible plants suggested for biosaline halophyte-based agriculture. After food production and harvesting of fresh leaves for food, the inedible plant fractions could be utilized to produce extracts rich in bioactive phytochemicals to maximize feedstock application and increase the economic feasibility of biomass processing to bioenergy. This study analyzed fresh juice and extracts from screw-pressed sea aster and sea fennel for their different phenolic compounds and pigment concentrations. Antioxidant and enzyme inhibition activities were also tested in vitro. Extracts from sea aster and sea fennel had phenolic contents up to 45.2 mgGAE/gDM and 64.7 mgGAE/gDM, respectively, and exhibited >70% antioxidant activity in several assays. Ethanol extracts also showed >70% inhibition activity against acetylcholinesterase and >50% inhibition of tyrosinase and α-glucosidase. Therefore, these species can be seen as potential feedstocks for further investigations.

Characterization of biochar produced from sewage sludge and its potential use as a substrate and plant growth improver.

Biochar is a product rich in carbon produced by pyrolysis of different kinds of biomass and it modifies the physical, chemical, and biological properties of soil. In this study, biochar, produced at different pyrolysis temperatures (590 °C, 665 °C, and 765 °C), was physico-chemically characterized. It was explored whether biochar made from sewage sludge can become an alternative solution for future water and phosphorus management in agricultural production. A pot experiment was conducted using Chinese cabbage (Brassica rapa subsp. pekinensis) to investigate the effect of applying different biochars to the substrate, taking into account different growth parameters and the biochemical composition of the plants, as well as the physico-chemical properties of the substrate. According to the results, pyrolysis temperature influences the content of elements in biochar and their availability to plants, with total phosphorus contents in biochar ranging from 4.6% to 4.9%. In addition, applying biochar to the substrate significantly increases the volumetric water content up to 4.5 fold more compared to the control, which indicates a promising application in drought stress conditions and, at the same time, is a source of nutrients and can help to reduce the amount of mineral fertilizer application.

Phenolic Compounds in Salicornia spp. and Their Potential Therapeutic Effects on H1N1, HBV, HCV, and HIV: A Review.

Despite public health risk mitigation measures and regulation efforts by many countries, regions, and sectors, viral outbreaks remind the world of our vulnerability to biological hazards and the importance of mitigation actions. The saltwater-tolerant plants in the Salicornia genus belonging to the Amaranthaceae family are widely recognized and researched as producers of clinically applicable phytochemicals. The plants in the Salicornia genus contain flavonoids, flavonoid glycosides, and hydroxycinnamic acids, including caffeic acid, ferulic acid, chlorogenic acid, apigenin, kaempferol, quercetin, isorhamnetin, myricetin, isoquercitrin, and myricitrin, which have all been shown to support the antiviral, virucidal, and symptom-suppressing activities. Their potential pharmacological usefulness as therapeutic medicine against viral infections has been suggested in many studies, where recent studies suggest these phenolic compounds may have pharmacological potential as therapeutic medicine against viral infections. This study reviews the antiviral effects, the mechanisms of action, and the potential as antiviral agents of the aforementioned phenolic compounds found in Salicornia spp. against an influenza A strain (H1N1), hepatitis B and C (HBV/HCV), and human immunodeficiency virus 1 (HIV-1), as no other literature has described these effects from the Salicornia genus at the time of publication. This review has the potential to have a significant societal impact by proposing the development of new antiviral nutraceuticals and pharmaceuticals derived from phenolic-rich formulations found in the edible Salicornia spp. These formulations could be utilized as a novel strategy by which to combat viral pandemics caused by H1N1, HBV, HCV, and HIV-1. The findings of this review indicate that isoquercitrin, myricetin, and myricitrin from Salicornia spp. have the potential to exhibit high efficiency in inhibiting viral infections. Myricetin exhibits inhibition of H1N1 plaque formation and reverse transcriptase, as well as integrase integration and cleavage. Isoquercitrin shows excellent neuraminidase inhibition. Myricitrin inhibits HIV-1 in infected cells. Extracts of biomass in the Salicornia genus could contribute to the development of more effective and efficient measures against viral infections and, ultimately, improve public health.

Isolation of Polyphenols from Aqueous Extract of the Halophyte Salicornia ramosissima.

Polyphenols from residual non-food grade Salicornia ramosissima have health-promoting effects in feed, food, or nutraceutical applications. Therefore, the isolation of polyphenols is of interest from a series of environmentally friendly isolation methods with recyclable solvents. The isolation of polyphenols from non-food grade S. ramosissima was investigated using sequential membrane filtration with and without acid pretreatment, liquid-liquid extraction, resin adsorption, and centrifugal partition chromatography (CPC); analyzed by the Folin-Ciocalteu assay for total polyphenols; and finally analyzed using UPLC-TQMS in negative ion-spray mode for detection of 14 polyphenols. Sequential membrane filtration and acid hydrolysis indicated the polyphenols forming complexes with other compounds, retaining the polyphenols in the retentate fraction of large molecular weight cut-off membrane sizes. Conventional liquid-liquid extraction using sequential ethyl acetate and n-butanol showed most polyphenols were extracted, apart from chlorogenic acids, indicating a low isolation efficiency of higher polarity polyphenols. Analysis of the extract after resin adsorption by Amberlite XAD-4 resin showed high efficiency for separation, with 100% of polyphenols adsorbed to the resin after 13 bed volumes and 96.7% eluted from the resin using ethanol. CPC fractionations were performed to fractionate the concentrated extract after resin adsorption. CPC fractionations of the 14 polyphenols were performed using an organic or aqueous phase as a mobile phase. Depending on the mobile phase, different compounds were isolated in a high concentration. Using these easily scalable methods, it was possible to comprehensively study the polyphenols of interest from S. ramosissima and their isolation mechanics. This study will potentially lead the way for the large-scale isolation of polyphenols from S. ramosissima and other complex halophytes. The compounds of the highest concentration after CPC fractionation were isoquercitrin and hyperoside (155.27 mg/g), chlorogenic acid (85.54 mg/g), cryptochlorogenic acid (101.50 mg/g), and protocatechuic acid (398.67 mg/g), and further isolation using CPC could potentially yield novel polyphenol nutraceuticals.

Risk-stratified selection to colonoscopy in FIT colorectal cancer screening: development and temporal validation of a prediction model.

BACKGROUND: Faecal immunochemical tests (FITs) yield many false positives and challenge colonoscopy capacity in colorectal cancer (CRC) screening programmes. We aimed to develop a risk-based selection of participants to undergo diagnostic colonoscopy. METHODS: The study was observational and used registry data from the Danish CRC screening programme. We included all participants invited 2014-2016 with a positive FIT (≥ 20 µg fHb/g) who underwent colonoscopy (n = 56,459). We predicted the risk of CRC or advanced neoplasia (AN) from age, gender and FIT value using logistic regression. We evaluated calibration and discrimination and conducted temporal validation. We compared the number of CRCs and adenomas identified by risk cut-offs and by a corresponding FIT cut-off. RESULTS: AUCs were 74.9% (95% CI: 73.6; 76.3) and 67.4% (95% CI: 66.8%; 68.0%) for the models predicting CRC and AN in the validation dataset. The cut-off of CRC risk calculated from age, gender and FIT value identified 1.03 times (95% CI: 1.02; 1.05) more CRCs and 1.01 times (95% CI: 1.01; 1.01) more medium/high-risk adenomas compared with the corresponding FIT cut-off. CONCLUSIONS: With existing data, risk-stratified FIT screening using a risk cut-off instead of a FIT cut-off can slightly improve the selection to colonoscopy of those at highest risk of cancer and adenomas.

Oral Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes.

BACKGROUND: Establishing cardiovascular safety of new therapies for type 2 diabetes is important. Safety data are available for the subcutaneous form of the glucagon-like peptide-1 receptor agonist semaglutide but are needed for oral semaglutide. METHODS: We assessed cardiovascular outcomes of once-daily oral semaglutide in an event-driven, randomized, double-blind, placebo-controlled trial involving patients at high cardiovascular risk (age of ≥50 years with established cardiovascular or chronic kidney disease, or age of ≥60 years with cardiovascular risk factors only). The primary outcome in a time-to-event analysis was the first occurrence of a major adverse cardiovascular event (death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke). The trial was designed to rule out 80% excess cardiovascular risk as compared with placebo (noninferiority margin of 1.8 for the upper boundary of the 95% confidence interval for the hazard ratio for the primary outcome). RESULTS: A total of 3183 patients were randomly assigned to receive oral semaglutide or placebo. The mean age of the patients was 66 years; 2695 patients (84.7%) were 50 years of age or older and had cardiovascular or chronic kidney disease. The median time in the trial was 15.9 months. Major adverse cardiovascular events occurred in 61 of 1591 patients (3.8%) in the oral semaglutide group and 76 of 1592 (4.8%) in the placebo group (hazard ratio, 0.79; 95% confidence interval [CI], 0.57 to 1.11; P<0.001 for noninferiority). Results for components of the primary outcome were as follows: death from cardiovascular causes, 15 of 1591 patients (0.9%) in the oral semaglutide group and 30 of 1592 (1.9%) in the placebo group (hazard ratio, 0.49; 95% CI, 0.27 to 0.92); nonfatal myocardial infarction, 37 of 1591 patients (2.3%) and 31 of 1592 (1.9%), respectively (hazard ratio, 1.18; 95% CI, 0.73 to 1.90); and nonfatal stroke, 12 of 1591 patients (0.8%) and 16 of 1592 (1.0%), respectively (hazard ratio, 0.74; 95% CI, 0.35 to 1.57). Death from any cause occurred in 23 of 1591 patients (1.4%) in the oral semaglutide group and 45 of 1592 (2.8%) in the placebo group (hazard ratio, 0.51; 95% CI, 0.31 to 0.84). Gastrointestinal adverse events leading to discontinuation of oral semaglutide or placebo were more common with oral semaglutide. CONCLUSIONS: In this trial involving patients with type 2 diabetes, the cardiovascular risk profile of oral semaglutide was not inferior to that of placebo. (Funded by Novo Nordisk; PIONEER 6 ClinicalTrials.gov number, NCT02692716.).

Gastrointestinal tolerability of once-weekly semaglutide 2.4 mg in adults with overweight or obesity, and the relationship between gastrointestinal adverse events and weight loss.

AIM: We evaluated gastrointestinal (GI) adverse events (AEs) with once-weekly semaglutide 2.4 mg in adults with overweight or obesity and their contribution to weight loss (WL). MATERIALS AND METHODS: AE analyses pooled data from the Semaglutide Treatment Effect in People With Obesity (STEP) 1-3 trials for participants randomized to 68 weeks of semaglutide 2.4 mg (n = 2117) or placebo (n = 1262). WL was analysed by presence/absence of GI AEs. Mediation analysis estimated WL effects mediated by and unrelated to GI AEs. GI tolerability with semaglutide 2.4 mg maintenance and cessation after dose escalation was evaluated using STEP 4 data among 803 participants tolerating 20 weeks of semaglutide run-in. RESULTS: GI AEs were more common with semaglutide 2.4 mg than placebo, with most frequently nausea (43.9% vs. 16.1% of participants), diarrhoea (29.7% vs. 15.9%), vomiting (24.5% vs. 6.3%) and constipation (24.2% vs. 11.1%). Most GI AEs with semaglutide were non-serious (99.5% of AEs), mild-to-moderate (98.1%), transient and occurred most frequently during/shortly after dose escalation. Few semaglutide-treated participants (4.3%) permanently discontinued treatment for GI AEs. In STEP 1-3, mean WL with semaglutide 2.4 mg was similar in participants without (9.6%-17.1%) versus with GI AEs (11.4%-17.7%). Consistent with this observation, mediation analysis found that GI AEs contributed little to semaglutide-induced WL: of the additional 7.6%-14.4% WL with semaglutide versus placebo, <1 percentage point was mediated by GI AEs. In STEP 4, semaglutide 2.4 mg maintenance was well tolerated. CONCLUSIONS: GI AEs were more common with semaglutide 2.4 mg than placebo, but typically mild-to-moderate and transient. Semaglutide-induced WL was largely independent of GI AEs.

Mental illness and participation in colorectal cancer screening: a scoping review.

INTRODUCTION: Compared with the background population, persons with mental illness have increased colorectal cancer (CRC) mortality. Screening has the potential to alleviate the increased cancer mortality due to mental illness, but the extent to which persons with mental illness participate in CRC screening programs is uncertain. This scoping review aims to summarize the literature on CRC screening participation among persons with mental illness. MATERIALS AND METHODS: We searched four databases (PubMed, PsychInfo, Embase, and the Cochrane Library) to identify published literature on mental illness and participation in CRC screening programs. We included full-text papers available in English, published before February 2021, and excluded papers on dementia, intellectual disabilities, and developmental disabilities. RESULTS: In total, we included 17 studies and categorized the findings according to severity of mental illness. Across varying study designs, the studies found that persons with severe mental illness, e.g. schizophrenia, participate less in CRC screening compared with the background population. The results were ambiguous for common mental illness, such as depression and anxiety. In general, studies were small or lacked comparison groups and the estimates were imprecise. CONCLUSION: This is the first scoping review to evaluate participation in CRC screening programs among persons with mental illness. Overall, the existing literature lacks high quality evidence from large population-based studies and comparison groups based on organized screening programs.

Chemical Profiling and Biological Activity of Extracts from Nine Norwegian Medicinal and Aromatic Plants.

There is an increased interest in identifying beneficial compounds of plant origin that can be added to animal diets to improve animal performance and have a health-promoting effect. In the present study, nine herb species of the Norwegian wild flora or which can be cultivated in Norway were selected for phytogenic evaluation (hops, maral root, mint, oregano, purslane, rosemary, roseroot, sweet wormwood, yarrow). Dried herbs were sequentially extracted with dichloromethane (DCM), ethanol (EtOH) and finally water (H2O) by ultrasound-assisted extraction (UAE). The UAE protocol was found to be more rational than conventional Soxhlet with respect to DCM extraction. Total extraction yield was found to be highest for oregano (Origanum vulgare) with 34.4 g 100-1 g dry matter (DM). H2O-extracts gave the highest yields of the three solvents, with up to 25 g 100-1 g DM for purslane (Portulaca oleracea ssp. sativa) and mint (Mentha piperita). EtOH- and H2O-extracts were the most efficient extracts with respect to free radical scavenging capacity (ABTS (=2,2-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid), and oregano, mint, hops (Humulus lupulus) and maral root-leaves (Leuzea carthamoides) were found to be the most efficient antioxidant sources. Hops (EtOH-extract) contained α- and ß-acids, xanthohumols, chlorogenic acid and the hitherto unreported 3-O-glucosides of kaempferol and quercetin. Maral root-leaves contained among other compounds hexosides of the 6-hydroxy- and 6-methoxy-kaempferol and -quercetin, whereas roseroot (Rosea rhodiola) revealed contents of rosavin, rhodiosin and rhodionin. Sweet wormwood (Artemisia annua) contained chlorogenic acid and several derivatives thereof, scopoletin and poly-methylated flavones (eupatin, casticin, chrysoplenetin). Antimicrobial potential of different plant extracts was demonstrated against Gram-positive and Gram-negative bacteria using the indicator organisms Staphylococcus aureus, and Escherichia coli, and the Atlantic salmon bacterial pathogens Moritella viscosa, Tenacibaculum finnmarkense and Aliivibrio wodanis. DCM extracts possessed the highest activities. Data demonstrate the potential ability of herb extracts as natural antimicrobials. However, future safety studies should be performed to elucidate any compromising effect on fish health.

Density calibrated cone beam CT as a tool for adaptive radiotherapy.

BACKGROUND: Visual inspections of anatomical changes observed on daily cone-beam CT (CBCT) images are often used as triggers for radiotherapy plan adaptation to avoid unacceptable dose levels to the target or OARs. Direct CBCT dose calculations would improve the ability to adapt only those plans where dosimetric changes are observed. This study investigates the accuracy of dose calculations on CBCTs. MATERIALS AND METHODS: Calibration curves were obtained for CBCT imagers at nine identical accelerators. CBCT scans of a phantom with different density inserts were recorded for two scan modes (Head-Neck and Pelvis) and mean calibration curves were calculated. Subsequently, CBCT scans of the phantom with six different density inserts were recorded, the dose distributions on the CBCTs were calculated and compared to dose on the planning CT (pCT). The uncertainty was quantified by the dosimetric difference between the pCT and the CBCT. The two mean calibration curves were used to calculate the daily delivered CBCT dose for ten Head-Neck-, eleven Lung-, and ten pelvic patients. Additional patient calculations were performed using low-HU empirically corrected calibration curves. Patient doses were compared on target coverage and mean dose, and D1cc for OARs. RESULTS: The dose differences between pCT and CBCT for phantom data were small for all DVH parameters, with mean deviations below ±0.6% for both CBCT modes. For patient data, it was found that low-HU corrected calibration curves performed the best. The mean deviations for the mean dose and coverage of the target were 0.2%±0.7% and 0.1%±0.6%, across all patient groups. CONCLUSION: Dose calculation on CBCT images results in target coverage and mean dose with an accuracy of the order of 1%, which makes this acceptable for clinical use. The CBCT mode specific calibration curves can be used at all identical imaging devices and for all patient groups.

Pharmacological Insights into Halophyte Bioactive Extract Action on Anti-Inflammatory, Pain Relief and Antibiotics-Type Mechanisms.

The pharmacological activities in bioactive plant extracts play an increasing role in sustainable resources for valorization and biomedical applications. Bioactive phytochemicals, including natural compounds, secondary metabolites and their derivatives, have attracted significant attention for use in both medicinal products and cosmetic products. Our review highlights the pharmacological mode-of-action and current biomedical applications of key bioactive compounds applied as anti-inflammatory, bactericidal with antibiotics effects, and pain relief purposes in controlled clinical studies or preclinical studies. In this systematic review, the availability of bioactive compounds from several salt-tolerant plant species, mainly focusing on the three promising species Aster tripolium, Crithmum maritimum and Salicornia europaea, are summarized and discussed. All three of them have been widely used in natural folk medicines and are now in the focus for future nutraceutical and pharmacological applications.

Variability of Major Phenyletanes and Phenylpropanoids in 16-Year-Old Rhodiola rosea L. Clones in Norway.

Rhodiola rosea L. (roseroot) is an adaptogen plant belonging to the Crassulaceae family. The broad spectrum of biological activity of R. rosea is attributed to its major phenyletanes and phenylpropanoids: rosavin, salidroside, rosin, cinnamyl alcohol, and tyrosol. In this study, we compared the content of phenyletanes and phenylpropanoids in rhizomes of R. rosea from the Norwegian germplasm collection collected in 2004 and in 2017. In general, the content of these bioactive compounds in 2017 was significantly higher than that observed in 2004. The freeze-drying method increased the concentration of all phenyletanes and phenylpropanoids in rhizomes compared with conventional drying at 70 °C. As far as we know, the content of salidroside (51.0 mg g-1) observed in this study is the highest ever detected in Rhodiola spp. Long-term vegetative propagation and high genetic diversity of R. rosea together with the freeze-drying method may have led to the high content of the bioactive compounds observed in the current study.

Cardiovascular safety of oral semaglutide in patients with type 2 diabetes: Rationale, design and patient baseline characteristics for the PIONEER 6 trial.

AIMS: To assess the cardiovascular (CV) safety of oral semaglutide, the first tablet formulation of a glucagon-like peptide-1 receptor agonist. MATERIALS AND METHODS: PIONEER 6 is a multinational, randomized, placebo-controlled, double-blind trial in patients with type 2 diabetes at high risk of CV events (defined as being aged ≥50 years and having established CV disease [CVD] or moderate [stage 3] chronic kidney disease [CKD], or being aged ≥60 years with ≥1 other CV risk factor). Patients were randomized to once-daily oral semaglutide (up to 14 mg) or placebo added to standard of care. The primary composite endpoint is time to first occurrence of CV death or non-fatal myocardial infarction or non-fatal stroke. The primary hypothesis was to exclude an excess in CV risk with oral semaglutide by assessing non-inferiority versus placebo for the primary endpoint (non-inferiority margin of 1.8 for the upper boundary of the 95% confidence interval of the hazard ratio). PIONEER 6 is event-driven, with follow-up continuing until accrual of at least 122 primary outcome events. There is no pre-defined minimal duration. RESULTS: Overall, 3183 patients have been enrolled (mean age 66.1 years, 31.6% females) in 214 sites across 21 countries. At baseline, the mean duration of diabetes was 14.9 years, mean glycated haemoglobin concentration was 66 mmol/mol (8.2%), and 84.6% of patients had established CVD/moderate CKD. CONCLUSIONS: PIONEER 6 will provide evidence regarding the CV safety of oral semaglutide in patients with type 2 diabetes and high CV risk.

Characterization and radiosensitivity of HPV-related oropharyngeal squamous cell carcinoma patient-derived xenografts.

Background: Oropharyngeal squamous cell carcinomas (OPSCC) are rising rapidly in incidence due to Human Papillomavirus (HPV) and/or tobacco smoking. Prognosis is better for patients with HPV-positive disease, but may also be influenced by tobacco smoking and other factors. There is a need to individualize treatment to minimize morbidity and improve prognosis. Patient-derived xenografts (PDX) is an emerging pre-clinical research model that may more accurately reflect the human disease, and is an attractive platform to study disease biology and develop treatments and biomarkers. In this study we describe the establishment of PDX models, compare PDX tumors to the human original, and assess the suitability of this model for radiotherapy research and biomarker development. Material and methods: Tumor biopsies from 34 patients with previously untreated OPSCC were implanted in immunodeficient mice, giving rise to 12 squamous cell carcinoma PDX models (7 HPV+, 5 HPV-). Primary and PDX tumors were characterized extensively, examining histology, immunohistochemistry, cancer gene sequencing and gene expression analysis. Radiosensitivity was assessed in vivo in a growth delay assay. Results: Established PDX models maintained histological and immunohistochemical characteristics as well as HPV-status of the primary tumor. Important cancer driver gene mutations, e.g., in TP53, PIK3CA and others, were preserved. Gene expression related to cancer stem cell markers and gene expression subtype were preserved, while gene expression related to hypoxia and immune response differed. Radiosensitivity studies showed high concordance with clinical observations. Conclusion: PDX from OPSCC preserves important molecular characteristics of the human primary tumor. Radiosensitivity were in accordance with clinically observed treatment response. The PDX model is a clinically relevant surrogate model of head and neck cancer. Perspectives include increased understanding of disease biology, which could lead to development of novel treatments and biomarkers.

Global Pediatric Drug Development.

BACKGROUND: The EU Paediatric Regulation was introduced in 2007. In the United States, specific paediatric legislation has existed for even longer. This overview describes the similarities and differences in the legislation and provides input on how to achieve a global, harmonized pediatric development plan. OBJECTIVES: The overview aims to investigate, through discussions and case examples, how to achieve pediatric medicines development fulfilling the expectations of the authorities as well as sponsors. METHODS: The pediatric legislation used in the European Union and United States are compared, and case studies for pediatric development plans where a global harmonized plan was eventually achieved are discussed. RESULTS: The case studies demonstrate some difficulties in getting to the goal of globally aligned pediatric plan development; however, recent initiatives from EMA and FDA are to a large degree addressing such challenges. CONCLUSIONS: Global pediatric drug development is a evolving field, and with recent initiatives from the European Medicines Agency and US Food and Drug Administration, this goal is definitively attainable. (Curr Ther Res Clin Exp. 2019; 80:XXX-XXX).

DBCG hypo trial validation of radiotherapy parameters from a national data bank versus manual reporting.

INTRODUCTION: The current study evaluates the data quality achievable using a national data bank for reporting radiotherapy parameters relative to the classical manual reporting method of selected parameters. METHODS: The data comparison is based on 1522 Danish patients of the DBCG hypo trial with data stored in the Danish national radiotherapy data bank. In line with standard DBCG trial practice selected parameters were also reported manually to the DBCG database. Categorical variables are compared using contingency tables, and comparison of continuous parameters is presented in scatter plots. RESULTS: For categorical variables 25 differences between the data bank and manual values were located. Of these 23 were related to mistakes in the manual reported value whilst the remaining two were a wrong classification in the data bank. The wrong classification in the data bank was related to lack of dose information, since the two patients had been treated with an electron boost based on a manual calculation, thus data was not exported to the data bank, and this was not detected prior to comparison with the manual data. For a few database fields in the manual data an ambiguity of the parameter definition of the specific field is seen in the data. This was not the case for the data bank, which extract all data consistently. CONCLUSIONS: In terms of data quality the data bank is superior to manually reported values. However, there is a need to allocate resources for checking the validity of the available data as well as ensuring that all relevant data is present. The data bank contains more detailed information, and thus facilitates research related to the actual dose distribution in the patients.

The potential benefits from respiratory gating for breast cancer patients regarding target coverage and dose to organs at risk when applying strict dose limits to the heart: results from the DBCG HYPO trial.

PURPOSE: The potential benefits from respiratory gating (RG) compared to free-breathing (FB) regarding target coverage and dose to organs at risk for breast cancer patients receiving post-operative radiotherapy (RT) in the DBCG HYPO multicentre trial are reported. MATERIAL AND METHODS: Patients included in the DBCG HYPO trial were randomized between 50 Gy in 25 fractions (normofractionated) versus 40 Gy in 15 fractions (hypofractionated). A tangential forward field-in-field dose planning technique was used to cover the clinical target volume (CTV) with the intent to limit dose to the left anterior descending coronary artery (LADCA) to 20 Gy and 17 Gy in the normo- and hypofractionated arms, respectively. Treatment plan data for 1327 patients from four Danish centres was retrospectively analyzed. FB right-sided patients served as control group for the left-sided patients regarding CTV V95% (relative volume receiving at least 95% of the prescribed dose), mean heart dose (MHD) and mean lung dose (MLD). RESULTS: Median CTV V95% was for FB right-sided, FB left-sided and RG left-sided patients 94.6, 92.6 and 94.7% for normofractionated therapy, respectively, and 94.6, 91.8 and 94.4% for hypofractionated therapy and did not differ significantly for RG left-sided plans compared to FB right-sided in either study arm. CTV V95% was significantly lower for FB versus RG for left-sided plans in both arms. Median MHD was 0.7, 1.8 and 1.5 Gy (normofractionated therapy) versus 0.6, 1.5 and 1.2 Gy (hypofractionated therapy), respectively. The corresponding median MLD was 9.0, 8.3 and 7.3 Gy versus 7.3, 6.4 and 5.8 Gy, respectively. CONCLUSIONS: RG for left-sided breast cancer patients ensured similar CTV V95% as for FB right-sided patients. MLD was lower for RG due to the increased lung volume. MHD was generally low due to strict protocol-defined maximum dose to LADCA, but for left-sided patients RG led to significantly lower MHD.

Wet fractionation of the succulent halophyte Salicornia sinus-persica, with the aim of low input (water saving) biorefining into bioethanol.

In this study Salicornia sinus-persica, a succulent halophyte was assessed for its potential to be used as a feedstock for bioethanol production. For such succulent, salty, green biomasses, direct fractionation and fermentation allow for water preservation in the process. Fresh biomass of S. sinus-persica was collected and split into two fractions by wet fractionation; liquid (juice) and solid (pulp). Sugar contents were found to be 1.0-1.5% for the juice fraction and 50% (w/w) for the fresh pulp. Direct fermentation of the juice using Saccharomyces cerevisiae showed no salt inhibition of the yeast and ethanol yields of ~70% were achieved. A pretreatment study was carried out for the pulp fraction applying mild hydrothermal pretreatment. Cellulose convertibility was found to be significantly higher for severity factors above 2.00, and the highest ethanol yield (76.91 ± 3.03%) was found at process severity of 3.06 (170 °C, 10 min).