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Glioblastoma (GBM) is the most aggressive primary brain tumor in adults, with a universally lethal prognosis despite maximal standard therapies. Here, we present a consensus treatment protocol based on the metabolic requirements of GBM cells for the two major fermentable fuels: glucose and glutamine. Glucose is a source of carbon and ATP synthesis for tumor growth through glycolysis, while glutamine provides nitrogen, carbon, and ATP synthesis through glutaminolysis. As no tumor can grow without anabolic substrates or energy, the simultaneous targeting of glycolysis and glutaminolysis is expected to reduce the proliferation of most if not all GBM cells. Ketogenic metabolic therapy (KMT) leverages diet-drug combinations that inhibit glycolysis, glutaminolysis, and growth signaling while shifting energy metabolism to therapeutic ketosis. The glucose-ketone index (GKI) is a standardized biomarker for assessing biological compliance, ideally via real-time monitoring. KMT aims to increase substrate competition and normalize the tumor microenvironment through GKI-adjusted ketogenic diets, calorie restriction, and fasting, while also targeting glycolytic and glutaminolytic flux using specific metabolic inhibitors. Non-fermentable fuels, such as ketone bodies, fatty acids, or lactate, are comparatively less efficient in supporting the long-term bioenergetic and biosynthetic demands of cancer cell proliferation. The proposed strategy may be implemented as a synergistic metabolic priming baseline in GBM as well as other tumors driven by glycolysis and glutaminolysis, regardless of their residual mitochondrial function. Suggested best practices are provided to guide future KMT research in metabolic oncology, offering a shared, evidence-driven framework for observational and interventional studies., Competing Interests: Declarations. Ethics approval and consent to participate: Not applicable. Consent for publication: Not applicable. Competing interests: A.P. is an owner of Poff Medical Consulting and Communications, LLC, which performs consulting and public speaking services related to ketogenic metabolic therapy. A.P. is a scientific advisor to Pruvit Ventures, LLC, which sells exogenous ketone products. A.P. is an owner of Metabolic Health Initiative, LLC which is a medical education company in the field of metabolic health and metabolism-based therapies. A.P. is an inventor on and receives royalties from the following patent: “Targeting Cancer with Metabolic Therapy and Hyperbaric Oxygen” (Patent Number: 9801903). D.P.D. is an inventor of patents on the use of exogenous ketones, advisor for Levels Health, and co-owner of Ketone Technologies LLC, which does consulting and public speaking events. C.E.C. receives royalties from books, consulting, and lectures on nutrition and exercise, and serves on the scientific advisory board of Simply Good Foods/Atkins. M.K. is employed by Dietary Therapies LLC. The other authors declare no competing interests., (© 2024. The Author(s).)

Background: Ketogenic diets (KDs) are high-fat diets with putative anti-tumor effects. The aim of this study was to synthesize the evidence for the anti-tumor effects of KDs in mice, with a focus on their possible synergism with chemotherapy (CT), radiotherapy (RT), or targeted therapies (TT)., Methods: Relevant studies were retrieved from a literature search. A total of 43 articles reporting on 65 mouse experiments fulfilled the inclusion criteria, and 1755 individual mouse survival times were collated from the study authors or the publications. The restricted mean survival time ratio (RMSTR) between the KD and control groups served as the effect size. Bayesian evidence synthesis models were used to estimate pooled effect sizes and to assess the impact of putative confounders and synergism between KD and other therapies., Results: Overall, there was a significant survival-prolonging effect of KD monotherapy (RMSTR = 1.161 ± 0.040), which was confirmed in meta-regression accounting for syngeneic versus xenogeneic models, early versus late KD start and subcutaneous versus other organ growth. Combining the KD with RT or TT, but not CT, was associated with a further 30% (RT) or 21% (TT) prolongation of survival. An analysis accounting for 15 individual tumor entities showed that KDs exerted significant survival-prolonging effects in pancreatic cancer (all treatment combinations), gliomas (KD + RT and KD + TT), head and neck cancer (KD + RT), and stomach cancer (KD+RT and KD + TT)., Conclusions: This analytical study confirmed the overall anti-tumor effects of KDs in a large number of mouse experiments and provides evidence for synergistic effects with RT and TT., (© 2023 Chang Gung University. Publishing services provided by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).)

Over the past two decades, it has been established that cancer patients with oligometastases, i.e., only a few detectable metastases confined to one or a few organs, may benefit from an aggressive local treatment approach such as the application of high-precision stereotactic body radiotherapy (SBRT). Specifically, some studies have indicated that achieving long-term local tumor control of oligometastases is associated with prolonged overall survival. This motivates investigations into which factors may modify the dose-response relationship of SBRT by making metastases more or less radioresistant. One such factor relates to the uptake of the positron emission tomography tracer 2-deoxy-2-[ 18 F]fluoro-D-glucose (FDG) which reflects the extent of tumor cell glycolysis or the Warburg effect, respectively. Here we review the biological mechanisms how the Warburg effect drives tumor cell radioresistance and metastasis and draw connections to clinical studies reporting associations between high FDG uptake and worse clinical outcomes after SBRT for oligometastases. We further review the evidence for distinct metabolic phenotypes of metastases preferentially seeding to specific organs and their possible translation into distinct radioresistance. Finally, evidence that obesity and hyperglycemia also affect outcomes after SBRT will be presented. While delivered dose is the main determinant of a high local tumor control probability, there might be clinical scenarios when metabolic targeting could make the difference between achieving local control or not, for example when doses have to be compromised in order to spare neighboring high-risk organs, or when tumors are expected to be highly therapy-resistant due to heavy pretreatment such as chemotherapy and/or radiotherapy., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: To describe the case of successful radiotherapeutic treatment of a woman suffering from Brooke-Spiegler syndrome who had multiple disfiguring cylindromas on the entire scalp and further tumors on the trunk., Methods: After decades of treatment with conventional therapies including surgery and topically applied salicylic acid, the 73-year-old woman agreed to undergo radiotherapeutic treatment. She received 60 Gy to the scalp and 36 Gy to painful nodules in the lumbar spine region., Results: Over a follow-up period of 14 and 11 years, respectively, the scalp nodules almost completely regressed, while the lumbar nodules became painless and considerably smaller. Apart from alopecia, no late adverse effects of treatment remain., Conclusion: This case should remind us of the potential role that radiotherapy could play in treating Brooke-Spiegler syndrome. The required dose for treatment of such extensive disease is still a matter of debate due to the scarcity of radiotherapeutic experience. This case demonstrates that for scalp tumors, 30 × 2 Gy can result in long-term tumor control, while other dose prescriptions may be adequate for tumors in other locations., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

In a recent modeling study Watson et al. (Lancet Infect Dis 2022;3099:1-10) claim that Covid-19 vaccinations have helped to prevent roughly 14-20 million deaths in 2021. This conclusion is based on an epidemiological susceptible-exposed-infectious-recovered (SEIR) model trained on partially simulated data and yielding a reproduction number distribution which was then applied to a counterfactual scenario in which the efficacy of vaccinations was removed. Drawing on the meta-theory of Critical Realism, we point out several caveats of this model and caution against believing in its predictions. We argue that the absence of vaccinations would have significantly changed the causal tendencies of the system being modelled, yielding a different reproduction number than obtained from training the model on actually observed data. Furthermore, the model omits many important causal factors. Therefore this model, similar to many previous SEIR models, has oversimplified the complex interplay between biomedical, social and cultural dimensions of health and should not be used to guide public health policy. In order to predict the future in epidemic situations more accurately, continuously optimized dynamic causal models which can include the not directly tangible, yet real causal mechanisms affecting public health appear to be a promising alternative to SEIR-type models., Competing Interests: The authors declare that they have no conflicts of interest related to this publication., (© 2023 Elsevier Ltd. All rights reserved.)

Background & Aims: Body composition plays a crucial role in therapy adherence and the prognosis of cancer patients. The aim of this work was to compare four measurement methods for determining body composition regarding their validity, reliability and practicability in order to be able to draft a practical recommendation as to which method is most suitable as a standard measurement method in oncology., Methods: Fat mass (FM) and fat-free mass (FFM) was estimated for 100 breast cancer patients with ages of 18-70 years during a defined 20-week inpatient and outpatient rehabilitation process after primary therapy or follow-up rehabilitation. The four methods used were dual energy X-ray absorptiometry (DXA), bioelectrical impedance analysis (BIA), leg-to-leg BIA and near-infrared spectroscopy (NIRS). At baseline (t0) and after 20 weeks (t20) the agreement between the four body composition analysis methods was quantified by pairwise method comparisons using Bland-Altman bias and limits of agreement estimates, t-tests and Lin's concordance correlation coefficients (CCCs)., Results: CCCs and Bland-Altman plots indicated that DXA and BIA, DXA and NIRS as well as BIA and NIRS showed an excellent agreement concerning FM estimation at both time points (CCC>0.9). In contrast, no methods agreed with a CCC higher than 0.9 with respect to FFM estimation. However, most estimates were also significantly different between two methods, except for BIA and NIRS which yielded comparable FFM and FM estimates at both time points, albeit with large 95% limits of agreement intervals. The agreement between DXA and BIA was best in the lowest BMI tertile and worsened as BMI increased. Significant differences were also found for FFM changes measured with DXA versus BIA (mean difference -0.4 kg, p = 0.0049), DXA versus to Leg-to-leg BIA (-0.6 kg, p = 0.00073) and for FM changes measured with DXA versus Leg-to-leg BIA (0.5 kg, p = 0.0011)., Conclusions: For accurate and valid body composition estimates, Leg-to-leg BIA cannot be recommended due to its significant underestimation of FM or significant overestimation of FFM, respectively. BIA and NIRS results showed good agreement with the gold standard DXA. Therefore both measurement methods appear to be very well suitable to assess body composition of oncological patients and should be used more frequently on a routine basis to monitor the body composition of breast cancer patients., Competing Interests: Conflict of interest There are neither (direct/indirect) financial nor personal relationships as well as no academic competitions or conflicts according personal beliefs., (Copyright © 2023 European Society for Clinical Nutrition and Metabolism. Published by Elsevier Ltd. All rights reserved.)

Introduction: Anxiety, burnout, and depression cause a substantial psychological and social burden. Bioenergetic meditation (BM) was developed by Viktor Philippi as a method to strengthen psychological and physical health. This work presents the results of four feasibility studies investigating the effects of BM developed by Viktor Philippi as a support for people suffering from these psychological disorders., Materials and Methods: A total of four prospective, non-randomized feasibility studies were conducted (N1 = 185, N2 = 140, N3 = 33, N4 = 32). Studies 1 and 2 were multicentric studies with a pre-post comparison consisting of 10 BMs within 10 weeks with individual study start and end points. Studies 3 and 4 consisted of 7 BMs within 3 days with a pre-post evaluation and follow-up measurements at 6, 12, and 18 months. The Beck Anxiety Inventory (BAI), Beck Depression Inventory (BDI-II), and Hamburg Burnout Inventory (HBI) were used to measure symptoms of anxiety, depression, and burnout, respectively., Results: After 10 BMs within 10 weeks, highly reliable decreases in symptoms of depression occurred in 58-73% of cases (p < 0.005). The median BDI-II score declined significantly by 60% (p < 0.0001) after 10 weeks of BM. Symptoms of anxiety were highly reliably reduced in roughly one-third of cases after 10 weekly BMs, with the average total BAI score declining from a severe to a moderate anxiety (p < 0.0001). The HBI showed significant improvement in all subscales. Psychological symptoms also improved significantly after 7 BMs, and symptom reductions classified as highly reliable were maintained until 18-months follow-up in more than 50% of participants., Conclusion: BM results in significant and lasting improvements in clinical symptoms of anxiety, depression, and burnout. Further studies including control groups are necessary to confirm these findings and determine any BM-specific effects., (© 2022 S. Karger AG, Basel.)

In this systematic review and meta-analysis of clinical controlled trials (CCTs) we aimed to investigate the efficacy of KDs as an adjuvant therapy on cardiometabolic outcomes in patient with cancer compared to conventional non-ketogenic diets. Only CCTs involving cancer patients that were assigned to either a KD or a standard diet control group were selected. Two reviewers independently extracted the data, and a meta-analysis was performed using a random effects model to estimate weighted mean differences (WMDs) and confidence intervals (CIs) in body composition, metabolite, lipid profile, liver and kidney function parameters and quality of life. This meta-analysis showed a significant reduction in body weight (WMD= -2.99 kg; 95% CI: -4.67, -1.31; and P  < 0.001), BMI (WMD= -1.08 kg/m 2 ; 95% CI: -1.81, -0.34; P  ≤ 0.002) and fat mass (WMD= -1.48 kg; 95% CI: -2.56, -0.40; and P  = 0.007) by a KD. KDs significantly decreased glucose (WMD= -5.22 mg/dl; 95% CI: -9.0, -1.44; and P  = 0.007), IGF-1 (WMD= -17.52 ng/ml; 95% CI: -20.24, -14.8; and P ˂0.001) and triglyceride (WMD= -24.46 mg/dl; 95% CI: -43.96, -4.95; and P  = 0.014) levels. Furthermore, KDs induced ketosis by increasing β-hydroxybutyrate (WMD= 0.56 mmol/l; 95% CI: 0.37, 0.75; and P  < 0.001). There were non-significant pooled effects of KDs on improving insulin, C-reactive protein and cholesterol levels and kidney and liver function. Emotional functioning was even increased significantly in the KD compared to the SD groups. In summary we found that KDs result in a greater reduction in glucose, IGF-1, triglycerides, body weight, BMI, and fat mass in cancer patients compared to traditional non-ketogenic diets and improved emotional functioning. The quality of evidence in the meta-analysis was moderate according to the Nutrigrade assessment.

Purpose: Patients with head and neck cancer (HNC) are at risk of malnutrition, especially during radiochemotherapy. We aimed to study the impact of a ketogenic diet (KD) versus an unspecified standard diet (SD) on body composition and survival in HNC patients undergoing radio(chemo)therapy., Methods: As part of a controlled clinical trial, non-metastasized HNC patients were enrolled into either a KD (N = 11) or an SD (N = 21) group between May 2015 and May 2021. Body composition was measured weekly by bioimpedance analysis and analyzed using linear mixed effects models. Overall and progression-free survival was assessed during regular follow-up., Results: A total of 7 KD and 21 SD patients completed the study and were eligible for comparative analysis. Chemotherapy was significantly associated with declines in all body composition parameters, while the KD had opposing, yet nonsignificant effects. In patients receiving chemotherapy, average weekly reductions of body mass (BM) and skeletal muscle mass (SMM) were 0.9 kg and 0.31 kg in the KD group versus 1.2 kg and 0.57 kg in the SD group, respectively. Patients in the KD group receiving no chemotherapy achieved an average increase of 0.04 kg BM and 0.12 kg SMM per week. After a median follow-up of 42 months (range 6.7-78 months) there were no significant differences in progression-free or overall survival between the groups., Conclusion: The KD may partially counteract the detrimental effects of radiochemotherapy on body composition in HNC patients. This should encourage further research into KDs in frail cancer patient populations and motivate their implementation as complementary therapy for selected patients., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Background TheWorld Economic Forum (WEF) has spawned a global network of elites called Young Global Leaders (YGLs) with significant influence on large corporations, politics, academia, and media. This article scrutinizes the idea that through this network, the WEF had a significant influence on the scale and scope of the non-pharmaceutical interventions (NPIs) implemented in response to the COVID-19 crisis. We tested for associations between the country-level distribution of YGLs and the intensity and duration of the implemented NPIs summarized by the Government Response Severity Index (GRSI). Materials and methods The number and category of YGLs per country was extracted from the WEF website. We also extracted the maximum and median GRSI values for three time periods: (i) the beginning of the first wave of the pandemic (March 1, 2020, to April 30, 2020), (ii) the height of the second wave in Europe (December 1, 2020, to January 31, 2021), and (iii) the approximate first year (March 1, 2020, to January 31, 2021). Being a precondition for causality, any association between the total or category-specific number of YGLs and the GRSI values in each time period was evaluated using Spearman's ρ correlation coefficients and polynomial regression, respectively. Results There was a highly significant positive correlation between the total number of YGLs in a country and the median (ρ = 0.36, p = 2.5×10 -7 ) and maximum (ρ = 0.34, p = 1.6×10 -6 ) GRSI during the second wave of the pandemic, but not during the first wave. The total number of YGLs was also a significant predictor of higher median GRSI during the second wave of the pandemic in the best-fitting (four-degree) polynomial regression model (p<0.01); additional significant and positive predictor in this model was a country's location within Europe or South America, respectively (p<0.01). Investigating an influence-weighted number of YGLs in business, politics, and civic society separately yielded no significant associations with NPI severity for any of the three time periods. Conclusions As there were significant correlations during the second, but not the first wave of the pandemic, we conclude that the WEF might not have been the origin of but rather an echo-chamber or amplifier for certain opinions and strategies that were formed and implemented during or before the first months of the COVID-19 crisis. Future qualitative studies may reveal putative causal mechanisms underlying our observed correlations., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2022, Klement et al.)

Objective: To answer the question: Why do people consent to being vaccinated with novel vaccines against SARS-CoV-2?, Design: Representative survey., Setting: Online panel., Participants: 1032 respondents of the general German population., Method: A representative survey among German citizens in November/December 2021 that resulted in 1032 complete responses on vaccination status, sociodemographic parameters and opinions about the COVID-19 situation., Results: Almost 83% of the respondents were vaccinated. The major motivation was fear of medical consequences of an infection and the wish to lead a normal life again. The major motivation to be not vaccinated was the fear of side effects and scepticism about long-term effectiveness and safety. Sixteen per cent of vaccinated respondents reported some serious side effect, while more than 30% reported health improvements, mostly due to the relief of psychological stress and social reintegration. We also validated a 'Corona Orthodoxy Score-COS' consisting of seven items reflecting opinions on COVID-19. The scale is reliable (alpha=0.76) and unidimensional. The COS was a highly significant predictor of vaccination status and readiness to be vaccinated in a multivariable logistic regression model. Those who were vaccinated were more likely to live in smaller households (OR=0.82, p=0.024), had a higher income (OR=1.27, p<0.001), a higher COS score (OR 1.4, p<0.0001) and used less alternative media (OR=0.44, p=0.0024) and scientific publications (OR=0.42, p=0.011) as information sources., Conclusions: The major motives for being vaccinated are fear of medical symptoms and the wish to lead a normal life. Those not wanting to be vaccinated cite a lack of knowledge regarding long-term safety and side effects as reasons. This can likely only be overcome by careful and active long-term efficacy and safety monitoring., Competing Interests: Competing interests: MH is the CEO of the company that conducted the survey. HW held an endowed chair sponsored by Heel pharmaceutical company, a producer of homeopathic remedies., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Aim: To clarify the high variability in COVID-19-related deaths during the first wave of the pandemic, we conducted a modeling study using publicly available data., Materials and Methods: We used 13 population- and country-specific variables to predict the number of population-standardized COVID-19-related deaths in 43 European countries using generalized linear models: the test-standardized number of SARS-CoV-2-cases, population density, life expectancy, severity of governmental responses, influenza-vaccination coverage in the elderly, vitamin D status, smoking and diabetes prevalence, cardiovascular disease death rate, number of hospital beds, gross domestic product, human development index and percentage of people older than 65 years., Results: We found that test-standardized number of SARS-CoV-2-cases and flu vaccination coverage in the elderly were the most important predictors, together with vitamin D status, gross domestic product, population density and government response severity explaining roughly two-thirds of the variation in COVID-19 related deaths. The latter variable was positively, but only weakly associated with the outcome, i.e., deaths were higher in countries with more severe government response. Higher flu vaccination coverage and low vitamin D status were associated with more COVID-19 related deaths. Most other predictors appeared to be negligible., Conclusion: Adequate vitamin D levels are important, while flu-vaccination in the elderly and stronger government response were putative aggravating factors of COVID-19 related deaths. These results may inform protection strategies against future infectious disease outbreaks., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Klement and Walach.)

Competing Interests: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Purpose: Interest in ketogenic diets (KDs) as complementary nutritional treatments for cancer patients is rising, although some skepticism about their safety exists. We, therefore, studied the effects of KDs on quality of life and blood parameters in rectal cancer patients undergoing radio-chemotherapy., Methods: EORTC-QLQ30 questionnaire scores and different metabolic and hormonal blood parameters were obtained prior to, in the middle of and at the end of radiotherapy within the KETOCOMP study (ClinicalTrials.gov Identifier: NCT02516501). A total of 18 patients consuming a KD were compared to 23 patients consuming their standard diet (SD). Baseline-end differences were measured using Wilcoxon tests, and repeated measures analysis was performed using linear mixed effects models., Results: Eighty-nine percent of patients on the KD reported subjectively feeling good or very good, but roughly half of them rated the daily routine implementation as difficult. Only the SD group experienced significant declines in physical and role functioning, while the KD group improved in role (p = 0.045), emotional (p = 0.018) and social functioning (p = 0.009).Urinary frequency, buttock pain and fatigue significantly increased in the SD group, but to a much lesser extent in the KD group. Several biomarkers of metabolic health (gamma-glutamyl-transpeptidase, triglyceride-glucose index, HDL cholesterol/triglyceride ratio, and free T3) improved in the KD, but not the SD group., Conclusions: Despite being perceived as difficult to implement by ≈50% of patients, KDs are feasible as complementary therapies alongside radio-chemotherapy and associated with subjective well-being. The hypothesis that they exert beneficial effects on quality of life and metabolic health in rectal cancer patients is supported by our data., Trial Registration: ClinicalTrials.gov identifier NCT02516501, registered Aug 6th 2015., (© 2021. Springer-Verlag GmbH Germany, part of Springer Nature.)

Background and Purpose: The standard treatment of glioblastoma patients consists of surgery followed by normofractionated radiotherapy (NFRT) with concomitant and adjuvant temozolomide chemotherapy. Whether accelerated hyperfractionated radiotherapy (HFRT) yields comparable results to NFRT in combination with temozolomide has only sparsely been investigated. The objective of this study was to compare NFRT with HFRT in a multicenter analysis., Materials and Methods: A total of 484 glioblastoma patients from four centers were retrospectively pooled and analyzed. Three-hundred-ten and 174 patients had been treated with NFRT (30 × 1.8 Gy or 30 × 2 Gy) and HFRT (37 × 1.6 Gy or 30 × 1.8 Gy twice/day), respectively. The primary outcome of interest was overall survival (OS) which was correlated with patient-, tumor- and treatment-related variables via univariable and multivariable Cox frailty models. For multivariable modeling, missing covariates were imputed using multiple imputation by chained equations, and a sensitivity analysis was performed on the complete-cases-only dataset., Results: After a median follow-up of 15.7 months (range 0.8-88.6 months), median OS was 16.9 months (15.0-18.7 months) in the NFRT group and 14.9 months (13.2-17.3 months) in the HFRT group (p = 0.26). In multivariable frailty regression, better performance status, gross-total versus not gross-total resection, MGMT hypermethylation, IDH mutation, smaller planning target volume and salvage therapy were significantly associated with longer OS (all p < 0.01). Treatment differences (HFRT versus NFRT) had no significant effect on OS in either univariable or multivariable analysis., Conclusions: Since HFRT with temozolomide was not associated with worse OS, we assume HFRT to be a potential option for patients wishing to shorten their treatment time., (© 2021. The Author(s).)

We investigate the epistemological consequences of a positive polymerase chain reaction SARS-CoV test for two relevant hypotheses: (i) V is the hypothesis that an individual has been infected with SARS-CoV-2; (ii) C is the hypothesis that SARS-CoV-2 is the cause of flu-like symptoms in a given patient. We ask two fundamental epistemological questions regarding each hypothesis: First, how much confirmation does a positive test lend to each hypothesis? Second, how much evidence does a positive test provide for each hypothesis against its negation? We respond to each question within a formal Bayesian framework. We construe degree of confirmation as the difference between the posterior probability of the hypothesis and its prior, and the strength of evidence for a hypothesis against its alternative in terms of their likelihood ratio. We find that test specificity-and coinfection probabilities when making inferences about C-were key determinants of confirmation and evidence. Tests with < 87% specificity could not provide strong evidence (likelihood ratio > 8) for V against ¬V regardless of sensitivity. Accordingly, low specificity tests could not provide strong evidence in favor of C in all plausible scenarios modeled. We also show how a positive influenza A test disconfirms C and provides weak evidence against C in dependence on the probability that the patient is influenza A infected given that his/her symptoms are not caused by SARS-CoV-2. Our analysis points out some caveats that should be considered when attributing symptoms or death of a positively tested patient to SARS-CoV-2., (© 2020. Springer Nature B.V.)

To report outcome (freedom from local progression [FFLP], overall survival [OS] and toxicity) after stereotactic, palliative or highly conformal fractionated (>12) radiotherapy (SBRT, Pall-RT, 3DCRT/IMRT) for adrenal metastases in a retrospective multicenter cohort within the framework of the German Society for Radiation Oncology (DEGRO). Adrenal metastases treated with SBRT (≤12 fractions, biologically effective dose [BED10] ≥ 50 Gy), 3DCRT/IMRT (>12 fractions, BED10 ≥ 50 Gy) or Pall-RT (BED10 < 50 Gy) were eligible for this analysis. In addition to unadjusted FFLP (Kaplan-Meier/log-rank), we calculated the competing-risk-adjusted local recurrence rate (CRA-LRR). Three hundred twenty-six patients with 366 metastases were included by 21 centers (median follow-up: 11.7 months). Treatment was SBRT, 3DCRT/IMRT and Pall-RT in 260, 27 and 79 cases, respectively. Most frequent primary tumors were non-small-cell lung cancer (NSCLC; 52.5%), SCLC (16.3%) and melanoma (6.7%). Unadjusted FFLP was higher after SBRT vs Pall-RT (P = .026) while numerical differences in CRA-LRR between groups did not reach statistical significance (1-year CRA-LRR: 13.8%, 17.4% and 27.7%). OS was longer after SBRT vs other groups (P < .05) and increased in patients with locally controlled metastases in a landmark analysis (P < .0001). Toxicity was mostly mild; notably, four cases of adrenal insufficiency occurred, two of which were likely caused by immunotherapy or tumor progression. Radiotherapy for adrenal metastases was associated with a mild toxicity profile in all groups and a favorable 1-year CRA-LRR after SBRT or 3DCRT/IMRT. One-year FFLP was associated with longer OS. Dose-response analyses for the dataset are underway., (© 2021 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of Union for International Cancer Control.)

Background & Aims: Obesity and low muscle mass are associated with worse outcomes of colorectal cancer patients. We conducted a controlled trial to study the impact of a ketogenic diet (KD) based on natural foods versus an unspecified standard diet (SD) on body composition in rectal cancer patients undergoing radiotherapy., Methods: Patients with non-metastasized rectal cancer were allocated to either the KD (N = 24) or the SD (N = 25) group during radiotherapy. Body composition was measured weekly by bioimpedance analysis and analyzed using linear mixed effects models. Pathologic response in patients undergoing neoadjuvant treatment was evaluated at the time of surgery., Results: A total of 18 KD and 23 SD patients completed the study and were eligible for analysis. The SD group experienced no noteworthy changes in any body composition parameter. In contrast, patients in the KD group lost significant amounts of body weight and fat mass, averaging 0.5 and 0.65 kg/week (p < 0.0001). There was a rapid loss of intracellular water consistent with initial intramuscular glycogen and water depletion, but skeletal muscle tissue was conserved. Pathological tumor responses were somewhat greater in the KD group, with a larger mean Dworak regression grade (p = 0.072) and larger percentage of near-complete (yT0N0 or yT1N1) responses (43 versus 15%, p = 0.116) that almost reached statistical significance in intention-to-treat analysis (50% versus 14%, p = 0.018)., Conclusions: In rectal cancer patients undergoing curative radiotherapy, a KD significantly reduced body weight and fat mass while preserving skeletal muscle mass. We could demonstrate a trend for KDs contributing synergistically to pathological tumor response, a finding in line with preclinical data that warrants future confirmation in larger studies., Trial Registration: ClinicalTrials.gov identifier: NCT02516501, registered on August 06, 2015., Competing Interests: Conflict of interest RJK has received an honorarium from the company vitaflo for giving a talk about the objectives and preliminary results of the KETOCOMP study. RJK, PSK and RAS follow a KD occasionally. No other potential conflicts of interest, in particular no financial conflicts of interest, exist. The companies providing product samples for this study had no influence on the design, data collection and analysis, and none of the authors has any business relationship with them., (Copyright © 2021 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Background : COVID-19 vaccines have had expedited reviews without sufficient safety data. We wanted to compare risks and benefits. Method : We calculated the number needed to vaccinate (NNTV) from a large Israeli field study to prevent one death. We accessed the Adverse Drug Reactions (ADR) database of the European Medicines Agency and of the Dutch National Register (lareb.nl) to extract the number of cases reporting severe side effects and the number of cases with fatal side effects. Result : The NNTV is between 200-700 to prevent one case of COVID-19 for the mRNA vaccine marketed by Pfizer, while the NNTV to prevent one death is between 9000 and 50,000 (95% confidence interval), with 16,000 as a point estimate. The number of cases experiencing adverse reactions has been reported to be 700 per 100,000 vaccinations. Currently, we see 16 serious side effects per 100,000 vaccinations, and the number of fatal side effects is at 4.11/100,000 vaccinations. For three deaths prevented by vaccination we have to accept two inflicted by vaccination. Conclusions : This lack of clear benefit should cause governments to rethink their vaccination policy.

Background & Aims: Ketogenic diets (KDs) have been proposed as complementary nutritional treatments for cancer patients. Because it is important to gain knowledge about the safety of KDs adopted during cancer therapy, we studied the effects of KDs on quality of life and blood parameters in women with early-stage breast cancer undergoing radiotherapy., Methods: A total of 29 patients consuming a KD were compared to 30 patients consuming their standard diet (SD) with respect to EORTC-QLQ30 questionnaire scores and different metabolic and hormonal blood parameters that were obtained prior to, in the middle of and at the end of radiotherapy. Baseline-to-end differences were assessed using Wilcoxon tests, and longitudinal changes were analyzed using linear mixed effects models., Results: Compared to the SD, women consuming a KD experienced significant improvements in emotional functioning, social functioning, sleep quality, future perspectives and systemic therapy side effects (all p-values <0.01). While breast symptoms increased significantly in both groups, the increase was less pronounced in the KD group. There was no hint of a detrimental effect of the KDs on either liver or kidney function; in contrast, biomarkers of metabolic health (gamma-glutamyl-transpeptidase, creatinine, triglycerides, IGF-1, free T3) significantly improved in the KD, but not the SD group., Conclusions: These data support the hypothesis that consuming a KD during radiotherapy is safe for women with breast cancer and has the potential to improve quality of life and metabolic health. CLINICALTRIALS., Gov Identifier: NCT02516501., Competing Interests: Conflict of interest All authors declare that they have no conflicts of interest associated with this research., (Copyright © 2021 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

The performance of diagnostic tests crucially depends on the disease prevalence, test sensitivity, and test specificity. However, these quantities are often not well known when tests are performed outside defined routine lab procedures which make the rating of the test results somewhat problematic. A current example is the mass testing taking place within the context of the world-wide SARS-CoV-2 crisis. Here, for the first time in history, laboratory test results have a dramatic impact on political decisions. Therefore, transparent, comprehensible, and reliable data is mandatory. It is in the nature of wet lab tests that their quality and outcome are influenced by multiple factors reducing their performance by handling procedures, underlying test protocols, and analytical reagents. These limitations in sensitivity and specificity have to be taken into account when calculating the real test results. As a resolution method, we have developed a Bayesian calculator, the Bayes Lines Tool (BLT), for analyzing disease prevalence, test sensitivity, test specificity, and, therefore, true positive, false positive, true negative, and false negative numbers from official test outcome reports. The calculator performs a simple SQL (Structured Query Language) query and can easily be implemented on any system supporting SQL. We provide an example of influenza test results from California, USA, as well as two examples of SARS-CoV-2 test results from official government reports from The Netherlands and Germany-Bavaria, to illustrate the possible parameter space of prevalence, sensitivity, and specificity consistent with the observed data. Finally, we discuss this tool's multiple applications, including its putative importance for informing policy decisions., Competing Interests: No competing interests were disclosed., (Copyright: © 2021 Aukema W et al.)

Vitamin D 3 (cholecalciferol) is a secosteroid and prohormone which is metabolized in various tissues to the biologically most active vitamin D hormone 1,25(OH) 2 D 3 (calcitriol). 1,25(OH) 2 D 3 has multiple pleiotropic effects, particularly within the immune system, and is increasingly utilized not only within prophylaxis, but also within therapy of various diseases. In this context, the latest research has revealed clinical benefits of high dose vitamin D 3 therapy in autoimmune diseases. The necessity of high doses of vitamin D 3 for treatment success can be explained by the concept of an acquired form of vitamin D resistance. Its etiology is based on the one hand on polymorphisms within genes affecting the vitamin D system, causing susceptibility towards developing low vitamin D responsiveness and autoimmune diseases; on the other hand it is based on a blockade of vitamin D receptor signaling, e.g. through pathogen infections. In this paper, we review observational and mechanistic evidence for the acquired vitamin D resistance hypothesis. We particularly focus on its clinical confirmation from our experience of treating multiple sclerosis patients with the so-called Coimbra protocol, in which daily doses up to 1000 I.U. vitamin D 3 per kg body weight can be administered safely. Parathyroid hormone levels in serum thereby provide the key information for finding the right dose. We argue that acquired vitamin D resistance provides a plausible pathomechanism for the development of autoimmune diseases, which could be treated using high-dose vitamin D 3 therapy., Competing Interests: DL and BS are certified Coimbra practitioners. BS owns the practice that apply the here described Coimbra protocol to patients with autoimmune diseases. The remaining authors declare that the research was conducted in the absense of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Lemke, Klement, Schweiger, Schweiger and Spitz.)

Breast cancer (BC) patients often ask for a healthy diet. Here, we investigated a healthy standard diet (SD), a low carb diet (LCD), and a ketogenic diet (KD) for BC patients during the rehabilitation phase. KOLIBRI was an open-label non-randomized one-site nutritional intervention trial, combining inpatient and outpatient phases for 20 weeks. Female BC patients ( n = 152; mean age 51.7 years) could select their diet. Data collected were: Quality of life (QoL), spiroergometry, body composition, and blood parameters. In total 30, 92, and 30 patients started the KD, LCD, and SD, respectively. Of those, 20, 76, and 25 completed the final examination. Patients rated all diets as feasible in daily life. All groups enhanced QoL, body composition, and physical performance. LCD participants showed the most impressive improvement in QoL aspects. KD participants finished with a very good physical performance and muscle/fat ratio. Despite increased cholesterol levels, KD patients had the best triglyceride/high-density lipoprotein (HDL) ratio and homeostatic model assessment of insulin resistance index (HOMA-IR). Most metabolic parameters significantly improved in the LCD group. SD participants ended with remarkably low cholesterol levels but did not improve triglyceride/HDL or HOMA-IR. In conclusion, both well-defined KDs and LCDs are safe and beneficial for BC patients and can be recommended during the rehabilitation phase.

Introduction: The use of cranial re-irradiation is growing with improving overall survival and the advent of high-precision radiotherapy techniques. Still the value of re-irradiation needs careful evaluation regarding safety and efficacy. We analyzed dosimetric and clinical data of patients receiving cranial re-irradiation using EQD2 sum plans., Methods and Material: We retrospectively analyzed the data of 76 patients who received repeated cranial radiotherapy from 02/2013 to 09/2016. 34 patients suffered from recurrent primary brain tumors, 42 from brain metastases. Dosimetric analysis was performed accumulating EQD2 dose distributions based on rigid image registration. Clinical and radiological data was collected at follow-ups including toxicity, local control and overall survival., Results: In total 76 patients had at least 2 courses of intracranial radiotherapy. The median accumulated prescription EQD2 dose was 96.5 Gy 2 for all radiation courses combined. The median D(0.1 cc) of the brain for patients receiving more than 100 Gy 2 was 114 Gy 2 with a highest dose of 161.5 Gy 2 . 74% of patients suffered from low grade (G1-G2) acute toxicity, only two high grade (>G3) toxicities were recorded.Median overall survival from the time of first re-irradiation was 57 weeks (range 4-186 weeks). The median time to local failure for patients with a primary brain tumor was not reached and 24 weeks (range 1-77 weeks) for patients with brain metastases., Conclusion: Repeated radiotherapy appears both safe and efficient in patients with recurrent primary or secondary brain tumors with doses to the brain up to 120 Gy 2 EQD2, doses below 100 Gy 2 for brainstem and doses below 75 Gy 2 EQD2 to chiasm and optic nerves., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 Published by Elsevier B.V. on behalf of European Society for Radiotherapy and Oncology.)

Background: Vitamin D has been shown to be associated with reduced risk and severity of COVID-19 and exerts regulating effects on all hallmarks of cancer. The goal of this study was to analyze the vitamin D status of a cancer patient cohort from our clinic in the Franconian region, Germany., Methods: 25-hydroxyvitamin D concentrations were available for 116 patients included in prospective trials in our clinic. Associations of vitamin D with anthropometric and blood parameters were investigated using Kendall's τ correlation coefficients and linear regression., Results: A total of 57 patients (49.1%) were vitamin D deficient (<20 ng/mL), and 92.2% did not meet the recommended vitamin D level of 40 ng/mL. There was a strong negative association between vitamin D and leukocyte count (τ = -0.173, p = 0.007) and C-reactive protein concentration (τ = -0.172, p = 0.007). In linear regression, the most important variables for predicting vitamin D levels were (in order of decreasing importance) season, fat mass index, platelet, and leukocyte count., Conclusions: Despite appeals towards medical societies to target widespread vitamin D deficiency in Germany more than 10 years ago, our data indicate that these have been without avail. Low vitamin D levels in cancer patients should be corrected using reasonable sun exposure and supplements., (© 2020 S. Karger AG, Basel.)

Evolutionary principles are rarely considered in clinical oncology. We here aimed to test the feasibility and effects of a dietary and physical activity intervention based on evolutionary considerations in an oncological setting. A total of 13 breast cancer patients referred to our clinic for curative radiotherapy were recruited for this pilot study. The women were supposed to undertake a "Paleolithic lifestyle" (PL) intervention consisting of a Paleolithic diet and daily outdoor activity of at least 30 min duration while undergoing radiotherapy. Body composition was measured weekly by bioimpedance analysis. Blood parameters were assessed before, during, and at the end of radiotherapy. A control group on an unspecified standard diet (SD) was assigned by propensity score matching. A total of eleven patients completed the study. The majority of patients (64%) reported feeling good or very good during the intervention. The intervention group experienced an average decrease of 0.4 kg body weight (p < 0.001) and 0.34 kg (p < 0.001) fat mass per week, but fat-free and skeletal muscle mass were not significantly affected. Vitamin D levels increased slightly from 23.8 (11-37.3) ng/ml to 25.1 (22.6-41.6) ng/ml (p = 0.053). β-hydroxybutyrate levels were significantly increased and triglycerides and free T3 hormone levels significantly reduced by the PL intervention. This pilot study shows that adoption of a PL intervention during curative radiotherapy of breast cancer patients is feasible and able to reduce fat mass. Daily outdoor activity could eliminate vitamin D deficiency (vitamin D < 20 ng/ml). Future studies are needed to confirm these findings.

Objectives: Calorie restriction (CR) >20% has been hypothesized to aid cancer prevention and treatment. Yet, to our knowledge, there is a lack of reported studies in humans describing tolerance, adherence, or efficacy, and unpublished and incomplete dietary studies may indicate lack of tolerability and compliance. The aim of this study was to assess registered clinical trials using CR for cancer treatment and prevention, rates of completion, and published reports to determine whether barriers to publication may be indicative of either negative studies, or incompletion due to unreported compliance issues., Methods: Current registered clinical trials assessing CR in cancer prevention and treatment were assessed at clinicaltrials.gov and the International Clinical Trials Registry at the World Health Organization. Assessment of study completion and publication was calculated and compared with methods of CR used, as were rates of inactive and incomplete studies, dormant studies, time of dormancy, type of study, and generalizable conclusions., Results: Twenty-nine trials were registered assessing CR in cancer treatment or prevention. Of these studies, 18 met initial criteria, and only 4 had completed and published results. Three of these tested a CR regimen incorporating exercise or intermittent restriction. Target CR ranged from 500 to 1000 kcal/d, with one study aim of 20% CR; no study reported rates of actual calorie intake. The majority of dormant and unpublished studies (69%) used general dietary CR and was without update ranging from 265 to 2518 d. Only one study reported on the side effects of the CR regimen; compliance and adherence to the regimen was described in the four completed studies that reported results. Only two studies were registered as pilot studies testing the feasibility of CR., Conclusions: Poor completion and lack of reporting of results is apparent in the majority of studies assessing CR for cancer prevention or treatment. These findings should be considered during the design of future studies assessing dietary strategies for cancer prevention or treatment., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Obesity and low muscle mass are associated with worse outcomes of breast cancer patients. We conducted a controlled trial to study the impact of a ketogenic diet (KD) based on natural foods versus an unspecified standard diet (SD) on body composition in breast cancer patients undergoing radiotherapy., Methods: Patients with non-metastasized breast cancer were allocated to either the KD (N = 32) or the SD (N = 31) during radiotherapy. Body composition was measured weekly by bioimpedance analysis. Blood parameters and quality of life were assessed before, during, and at the end of radiotherapy., Results: A total of 29 KD and 30 SD patients completed the study. During radiotherapy, mean and median fasting BHB concentrations in the KD group were 0.72 and 0.49 mmol/l (range 0.06-4.9) which was significantly higher than those in the SD group (p < 2.2 × 10 -16 ). There was a very small and insignificant increase in body weight and fat mass in the SD group, as well as a decrease of fat free mass. In contrast, patients in the KD group lost body weight and fat free and skeletal muscle mass quickly after diet onset, which for the most part was related to water losses. The KD did not cause further substantial changes in fat free or skeletal muscle mass, but was associated with a gradual decrease of 0.4 kg body weight and fat mass per week (p < 0.0001). The KD significantly decreased free T3 levels by 0.06 pg/ml/week (p = 6.3 × 10 -5 ). Global quality of life remained stable in the SD group but increased in the KD group from a score of 66.7 to 75.0 (p = 0.20)., Conclusions: In breast cancer patients undergoing curative radiotherapy, a KD based on natural foods is feasible. After initial water losses, the KD tends to reduce body weight and fat mass while preserving fat free and skeletal muscle mass., Trial Registration: ClinicalTrials.gov identifier: NCT02516501 , registered on August 06, 2015.

Background: Large variation regarding prescription and dose inhomogeneity exists in stereotactic body radiation therapy (SBRT) for early-stage non-small cell lung cancer. The aim of this modeling study was to identify which dose metric correlates best with local tumor control probability to make recommendations regarding SBRT prescription., Methods and Materials: We combined 2 retrospective databases of patients with non-small cell lung cancer, yielding 1500 SBRT treatments for analysis. Three dose parameters were converted to biologically effective doses (BEDs): (1) the (near-minimum) dose prescribed to the planning target volume (PTV) periphery (yielding BED min ); (2) the (near-maximum) dose absorbed by 1% of the PTV (yielding BED max ); and (3) the average between near-minimum and near-maximum doses (yielding BED ave ). These BED parameters were then correlated to the risk of local recurrence through Cox regression. Furthermore, BED-based prediction of local recurrence was attempted by logistic regression and fast and frugal trees. Models were compared using the Akaike information criterion., Results: There were 1500 treatments in 1434 patients; 117 tumors recurred locally. Actuarial local control rates at 12 and 36 months were 96.8% (95% confidence interval, 95.8%-97.8%) and 89.0% (87.0%-91.1%), respectively. In univariable Cox regression, BED ave was the best predictor of risk of local recurrence, and a model based on BED min had substantially less evidential support. In univariable logistic regression, the model based on BED ave also performed best. Multivariable classification using fast and frugal trees revealed BED max to be the most important predictor, followed by BED ave ., Conclusions: BED ave was generally better correlated with tumor control probability than either BED max or BED min . Because the average between near-minimum and near-maximum doses was highly correlated to the mean gross tumor volume dose, the latter may be used as a prescription target. More emphasis could be placed on achieving sufficiently high mean doses within the gross tumor volume rather than the PTV covering dose, a concept needing further validation., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Preclinical data provide evidence for synergism between ketogenic diets (KDs) and other oncological therapies. The aim of this systematic review was to summarize data from clinical studies that have tested KDs along with other treatments used within medical oncology. The PubMed database was searched using the key words "ketogenic" AND ("cancer" OR "glioblastoma"). A secondary search was conducted by screening the reference lists of relevant articles on this topic. Relevant studies for this review were defined as studies in which KDs were used complementary to surgery, radio-, chemo-, or targeted therapy and at least one of the following four outcomes were reported: (i) Overall survival (OS); (ii) progression-free survival (PFS); (iii) local control rate; (iv) body composition changes. Twelve papers reporting on 13 clinical studies were identified. Nine studies were prospective and six had a control group, but only two were randomized. KD prescription varied widely between studies and was described only rudimentarily in most papers. Adverse events attributed to the diet were rare and only minor (grade 1-2) except for one possibly diet-related grade 4 event. Studies reporting body composition changes found beneficial effects of KDs in both overweight and frail patient populations. Beneficial effects of KDs on OS and/or PFS were found in four studies including one randomized controlled trial. Studies in high-grade glioma patients were not sufficiently powered to prove efficacy. Evidence for beneficial effects of KDs during cancer therapy is accumulating, but more high-quality studies are needed to assess the overall strength of evidence.

Background: High-dose hypofractionated radiotherapy should theoretically result in a deviation from the typical linear-quadratic shape of the cell survival curve beyond a certain threshold dose, yet no evidence for this hypothesis has so far been found in clinical data of stereotactic body radiotherapy treatment (SBRT) for early-stage non-small cell lung cancer (NSCLC). A pragmatic explanation is a larger α/β ratio than the conventionally assumed 10 Gy. We here attempted an estimation of the α/β ratio for NSCLC treated with SBRT using individual patient data., Materials and Methods: We combined two large retrospective datasets, yielding 1294 SBRTs (≤10 fractions) of early stage NSCLC. Cox proportional hazards regression, a logistic tumor control probability model and a biologically motivated Bayesian cure rate model were used to estimate the α/β ratio based on the observed number of local recurrences and accounting for tumor size., Results: A total of 109 local progressions were observed after a median of 17.7 months (range 0.6-76.3 months). Cox regression, logistic regression of 3 year tumor control probability and the cure rate model yielded best-fit estimates of α/β = 12.8 Gy, 14.9 Gy and 12-16 Gy (depending on the prior for α/β), respectively, although with large uncertainties that did not rule out the conventional α/β = 10 Gy., Conclusions: Clinicians can continue to use the simple LQ formalism to compare different SBRT treatment schedules for NSCLC. While α/β = 10 Gy is not ruled out by our data, larger values in the range 12-16 Gy are more probable, consistent with recent meta-regression analyses., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Current standard of treatment for newly diagnosed patients with glioblastoma (GBM) is surgical resection with adjuvant normofractionated radiotherapy (NFRT) combined with temozolomide (TMZ) chemotherapy. Hyperfractionated accelerated radiotherapy (HFRT) which was known as an option from randomized controlled trials before the temozolomide era has not been compared to the standard therapy in a randomized setting combined with TMZ., Methods: Data of 152 patients with newly diagnosed GBM treated from 10/2004 until 7/2018 at a single tertiary care institution were extracted from a clinical database and retrospectively analyzed. Thirty-eight patients treated with NFRT of 60 Gy in 30 fractions (34 with simultaneous and 2 with sequential TMZ) were compared to 114 patients treated with HFRT of 54.0 Gy in 30 fraction of 1.8 Gy twice daily (109 with simultaneous and 3 with sequential TMZ). The association between treatment protocol and other variables with overall survival (OS) was assessed using univariable and multivariable Cox regression analysis; the latter was performed using variables selected by the LASSO method., Results: Median overall survival (OS) was 20.3 month for the entire cohort. For patients treated with NFRT median OS was 24.4 months compared to 18.5 months in patients treated with HFRT (p = 0.131). In univariable regression analysis the use of dexamethasone during radiotherapy had a significant negative impact on OS in both patient groups, HR 2.21 (95% CI 1.47-3.31, p = 0.0001). In multivariable analysis adjusted for O6-methylguanine-DNA methyl-transferase (MGMT) promotor methylation status, salvage treatment and secondary GBM, the use of dexamethasone was still a negative prognostic factor, HR 1.95 (95% CI 1.21-3.13, p = 0.006). Positive MGMT-methylation status and salvage treatment were highly significant positive prognostic factors. There was no strong association between treatment protocol and OS (p = 0.504)., Conclusions: Our retrospective analysis supports the hypothesis of equivalence between HFRT and the standard protocol of treatment for GBM. For those patients who are willing to obtain the benefit of shortening the course of radiochemotherapy, HFRT may be an alternative with comparable efficacy although it was not yet tested in a large prospective randomized study against the current standard. The positive influence of salvage therapy and negative impact of concomitant use of corticosteroids should be addressed in future prospective trials. To confirm our results, we plan to perform a pooled analysis with other tertiary clinics in order to achieve better statistical reliability.

Purpose: To identify frequency, clinical relevance and risk factors for vertebral compression fracture (VCF) after spine stereotactic body radiation therapy (SBRT) with long-term follow up (FU)., Methods: From 2012 to 2015, 61 lesions (56 patients) were treated within a prospective multicenter phase 2 study (NCT01594892) of SBRT for painful vertebral metastases. Post-SBRT VCF were identified. Anatomical segments, normal and tumor tissue of treated vertebrae were segmented for volumetric analyses. Predictive factors for VCF were identified by logistic regression., Results: Median clinical and radiological FU for all patients was 16.2 months (range, 0-68.2) and 7.8 months (range, 0-66.9), respectively. Local metastasis control was observed in 82% of lesions at last imaging FU. Post-SBRT VCF occurred in 21 lesions (34.4%): 16.4% showed a progressive VCF, while a new VCF occurred in 18.0%. 3/56 (5.4%) patients developed painful VCF defined as pain increase by ≥2 on the visual analogue scale (VAS) and 2 (3.6%) patients required surgical stabilization. Pre-SBRT VCF, localization in the thoracic spine, Bilsky score >0, SINS score, pre-SBRT osteolytic volume and metastatic vertebral body (VB) involvement were predictive factors for VCF on univariate analysis. Relative VB involvement, osteolytic volume and pre-SBRT VCF remained in the multivariate logistic regression model that had AUC = 0.930, 83.3% sensitivity and 96.6% specificity., Conclusion: Spine SBRT resulted in favorable long-term pain and local metastasis control. Despite post-SBRT VCF being observed after one third of treatments, this was symptomatic in only 5% of patients. Predictive factors for developing VCF were identified which could contribute to better selection of patients for spine SBRT., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Competing Interests: Conflict of interest statement: The authors declare that there is no conflict of interest.

Introduction: Studies have consistently identified an increased risk of pancreatic cancer in diabetics, yet the role hyperglycemia may play in predicting prognosis is less clear. This work aims to evaluate the impact of glycemic state and antidiabetics on outcomes after systemic and local treatment for locoregionally advanced pancreatic cancer., Materials and Methods: This retrospective study consisted of 303 patients with newly diagnosed advanced-stage pancreatic cancer treated from 2004 to 2014. Kaplan-Meier survival analysis method was used to estimate time to event for overall survival, distant metastasis, and locoregional control. Blood glucose values (n=8599) were assessed both as continuous and categorical variables in univariate and multivariable Cox proportional hazard regression models to estimate hazard ratios (HRs) and identify independent prognostic factors. A 6-month conditional landmark analysis excluding patients with <6 months follow-up or survival was conducted., Results: Median follow-up and survival was 18.1 and 18.4 months, respectively. On univariate analysis, maximum pretreatment glucose value was associated with reduced overall survival (HR 1.005, P=0.023) and locoregional control (HR 1.001, P=0.001). A pretreatment glucose value ≥200 mg/dL was associated with increased mortality in multivariable analysis (adjusted HR 1.01, P=0.015). After conditional analysis, glucose ≥200 mg/dL before local treatment was associated with reduced overall survival (adjusted HR 1.562; 95% confidence interval [CI], 1.16-2.11; P=0.003)., Conclusions: Elevated blood glucose before treatment of locoregionally advanced pancreatic cancer was associated with poorer outcomes. These findings should be incorporated in future clinical trial design.