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The present study examined the relationships between CT-derived muscle measurements, systemic inflammation, and survival in advanced cancer patients with good performance status (ECOG-PS 0/1). Data was collected prospectively from patients with advanced cancer undergoing anti-cancer therapy with palliative intent. The CT Sarcopenia score (CT-SS) was calculated by combining the CT-derived skeletal muscle index (SMI) and density (SMD). The systemic inflammatory status was determined using the modified Glasgow Prognostic Score (mGPS). The primary outcome of interest was overall survival (OS). Univariate and multivariate Cox regressions were used for survival analysis. Three hundred and seven patients met the inclusion criteria, out of which 62% (n = 109) were male and 47% (n = 144) were ≥65 years of age, while 38% (n = 118) were CT-SS ≥ 1 and 47% (n = 112) of patients with pre-study blood were inflamed (mGPS ≥ 1). The median survival from entry to the study was 11.1 months (1–68.1). On univariate analysis, cancer type (p < 0.05) and mGPS (p < 0.001) were significantly associated with OS. On multivariate analysis, only mGPS (p < 0.001) remained significantly associated with OS. In patients who were ECOG-PS 0, mGPS was significantly associated with CT-SS (p < 0.05). mGPS may dominate the prognostic value of CT-derived sarcopenia in good-performance-status patients with advanced cancer.

Introduction/Background: Second primary lung cancers (SPLC) are common following non-small cell lung cancer (NSCLC) treatment. Development of SPLC following stereotactic ablative radiation therapy (SABR) may differ as compared to surgical cohorts. We report incidence of and outcomes for SPLC detected by surveillance imaging in a cohort of patients treated with SABR. Materials/Methods: Patients treated with SABR for node-negative NSCLC between 02/2007-05/2019 were retrospectively identified. Patient characteristics, frequency of surveillance imaging, development of SPLC, recurrence patterns, and survival were reviewed. Surveillance CT was performed Q3-4 month year one, Q3-6 month year 2, Q6-12 month year 3-5, and Q12 month thereafter. Actuarial estimates of development of SPLC and overall survival (OS) were generated with competing risk analysis. Results: We identified 134 patients treated with SABR with ≥6 months follow up. Eighteen (13.4%) developed a total of 21 SPLC at a median of 28.5 months (range 3.0-84.7 months) following SABR, 19 (90.5%) biopsy-proven. Twenty (95.2%) SPLC were detected by surveillance imaging. Three patients developed 2 metachronous SPLC. Three and 5-year SPLC estimates were 11.7% and 13.1%. Eighteen (85.7%) SPLC were treated with curative intent. Two and 3-year estimate of OS following detection of SPLC was 79.8% and 54.7%. Conclusion: SPLC were more common in our cohort than other published studies. Outcomes following surveillance detected SPLC are similar to those of de novo early stage lung cancers. The high frequency of SPLC in our cohort suggests further studies to refine overall surveillance in very high-risk populations are needed.

Shows the biodistribution data for [18F]αvβ6-BP in mice bearing paired αvβ6-expressing DX3puroβ6 and non-αvβ6-expressing DX3puro xenograft tumors at 1, 2 and 4 h p.i. and at 1 h p.i. after pre-administration of blocking peptide. Tissue uptake is expressed as decay-corrected percent injected dose per gram of tissue (dc % ID/g)

Purpose:The study was undertaken to develop and evaluate the potential of an integrin αvβ6-binding peptide (αvβ6-BP) for noninvasive imaging of a diverse range of malignancies with PET.Experimental Design:The peptide αvβ6-BP was prepared on solid phase and radiolabeled with 4-[18F]fluorobenzoic acid. In vitro testing included ELISA, serum stability, and cell binding studies using paired αvβ6-expressing and αvβ6-null cell lines. In vivo evaluation (PET/CT, biodistribution, and autoradiography) was performed in a mouse model bearing the same paired αvβ6-expressing and αvβ6-null cell xenografts. A first-in-human PET/CT imaging study was performed in patients with metastatic lung, colon, breast, or pancreatic cancer.Results:[18F]αvβ6-BP displayed excellent affinity and selectivity for the integrin αvβ6 in vitro [IC50(αvβ6) = 1.2 nmol/L vs IC50(αvβ3) >10 μmol/L] in addition to rapid target-specific cell binding and internalization (72.5% ± 0.9% binding and 52.5% ± 1.8%, respectively). Favorable tumor affinity and selectivity were retained in the mouse model and excretion of unbound [18F]αvβ6-BP was rapid, primarily via the kidneys. In patients, [18F]αvβ6-BP was well tolerated without noticeable adverse side effects. PET images showed significant uptake of [18F]αvβ6-BP in both the primary lesion and metastases, including metastasis to brain, bone, liver, and lung.Conclusions:The clinical impact of [18F]αvβ6-BP PET imaging demonstrated in this first-in-human study is immediate for a broad spectrum of malignancies.

Describes additional methods

Shows the in vivo stability of [18F]αvβ6-BP in human blood. Representative radio-HPLC of blood sample taken 30 min post injection. Top: Sample only; bottom: sample spiked with [18F]αvβ6-BP. X-axis: retention time [min]; Y-axis: detector response [volts].

Persons with serious mental illnesses experience high rates of medical comorbidity, especially diabetes. This study examined initial implementation feasibility, acceptability, and appropriateness of a new 6-month Multicomponent Intervention for Diabetes risk reduction in Adults with Serious mental illnesses (MIDAS) among persons in residential care facilities (RCFs). We conducted a mixed-methods study using four types of quantitative and qualitative data sources (administrative data; structured facility-level observations; resident assessments including blood-based biomarkers, 24-h dietary recalls, and self-report physical activity; and focus groups/interviews with staff and participants), to assess evidence of and factors affecting intervention feasibility, acceptability, and appropriateness. It was feasible to provide a high percentage of MIDAS class sessions (mean 50 of 52 intended sessions delivered) and make nutrition-related RCF changes (substitutions for healthier food items and reduced portion sizes). Class attendance rates and positive feedback from residents and staff provided evidence of MIDAS acceptability and appropriateness for addressing identified health needs. The residents who attended ≥ 85% of the sessions had greater improvement in several desired outcomes compared to others. Implementing a fully integrated MIDAS model with more extensive changes to facilities and more fundamental health changes among residents was more challenging. While the study found evidence to support feasibility, acceptability, and appropriateness of individual MIDAS components, some challenges for full implementation and success in obtaining immediate health benefits were also apparent. The study results highlight the need for improving health among RCF populations and will inform MIDAS adaptations designed to improve intervention fit and effectiveness outcomes.

Since the 1990s, Veterans Health Administration (VHA) has maintained a registry of Veterans with Spinal Cord Injuries and Disorders (SCI/Ds) to guide clinical care, policy, and research. Historically, methods for collecting and recording data for the VHA SCI/D Registry (VSR) have required significant time, cost, and staffing to maintain, were susceptible to missing data, and caused delays in aggregation and reporting. Each subsequent data collection method was aimed at improving these issues over the last several decades. This paper describes the development and validation of a case-finding and data-capture algorithm that uses primary clinical data, including diagnoses and utilization across 9 million VHA electronic medical records, to create a comprehensive registry of living and deceased Veterans seen for SCI/D services since 2012. A multi-step process was used to develop and validate a computer algorithm to create a comprehensive registry of Veterans with SCI/D whose records are maintained in the enterprise wide VHA Corporate Data Warehouse. Chart reviews and validity checks were used to validate the accuracy of cases that were identified using the new algorithm. An initial cohort of 28,202 living and deceased Veterans with SCI/D who were enrolled in VHA care from 10/1/2012 through 9/30/2017 was validated. Tables, reports, and charts using VSR data were developed to provide operational tools to study, predict, and improve targeted management and care for Veterans with SCI/Ds. The modernized VSR includes data on diagnoses, qualifying fiscal year, recent utilization, demographics, injury, and impairment for 38,022 Veterans as of 11/2/2022. This establishes the VSR as one of the largest ongoing longitudinal SCI/D datasets in North America and provides operational reports for VHA population health management and evidence-based rehabilitation. The VSR also comprises one of the only registries for individuals with non-traumatic SCI/Ds and holds potential to advance research and treatment for multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), and other motor neuron disorders with spinal cord involvement. Selected trends in VSR data indicate possible differences in the future lifelong care needs of Veterans with SCI/Ds. Future collaborative research using the VSR offers opportunities to contribute to knowledge and improve health care for people living with SCI/Ds.

Background Although suggestive of dysregulated metabolism, the relationship between serum LDH level, phenotypic/aetiologic diagnostic Global Leadership Initiative on Malnutrition (GLIM) criteria and survival in patients with advanced cancer has yet to examined. Methods Prospectively collected data from patients with advanced cancer, undergoing anti-cancer therapy with palliative intent, across nine sites in the UK and Ireland between 2011–2016, was retrospectively analysed. LDH values were grouped as 500 Units/L. Relationships were examined using χ2 test for linear-by-linear association and binary logistics regression analysis. Results A total of 436 patients met the inclusion criteria. 46% (n = 200) were male and 59% (n = 259) were ≥65 years of age. The median serum LDH was 394 Units/L and 33.5% (n = 146) had an LDH > 500 Units/L. LDH was significantly associated with ECOG-PS (p p p p p p p p p p Discussion LDH was associated with performance status, systemic inflammation and survival in patients with advanced cancer. LDH measurement may be considered as an aetiologic criteria and become a potential therapeutic target in the treatment of cancer cachexia.

IntroductionWe investigated whether adding computed tomography (CT) and/or 18F-fluorodeoxyglucose (18F-FDG) PET radiomics features to conventional prognostic factors (CPFs) improves prognostic value in locally advanced non-small cell lung cancer (NSCLC).Materials and methodsWe retrospectively identified 39 cases with stage III NSCLC who received chemoradiotherapy and underwent planning CT and staging 18F-FDG PET scans. Seven CPFs were recorded. Feature selection was performed on 48 CT and 49 PET extracted radiomics features. A penalized multivariate Cox proportional hazards model was used to generate models for overall survival based on CPFs alone, CPFs with CT features, CPFs with PET features, and CPFs with CT and PET features. Linear predictors generated and categorized into 2 risk groups for which Kaplan-Meier survival curves were calculated. A log-rank test was performed to quantify the discrimination between the groups and calculated the Harrell's C-index to quantify the discriminatory power. A likelihood ratio test was performed to determine whether adding CT and/or PET features to CPFs improved model performance.ResultsAll 4 models significantly discriminated between the 2 risk groups. The discriminatory power was significantly increased when CPFs were combined with PET features (C-index 0.82; likelihood ratio test P < .01) or with both CT and PET features (0.83; P < .01) compared with CPFs alone (0.68). There was no significant improvement when CPFs were combined with CT features (0.68).ConclusionAdding PET radiomics features to CPFs yielded a significant improvement in the prognostic value in locally advanced NSCLC; adding CT features did not.

Although suggestive of dysregulated metabolism, the relationship between serum LDH level, phenotypic/aetiologic diagnostic Global Leadership Initiative on Malnutrition (GLIM) criteria and survival in patients with advanced cancer has yet to examined.Prospectively collected data from patients with advanced cancer, undergoing anti-cancer therapy with palliative intent, across nine sites in the UK and Ireland between 2011-2016, was retrospectively analysed. LDH values were grouped as250/250-500/500 Units/L. Relationships were examined using χA total of 436 patients met the inclusion criteria. 46% (n = 200) were male and 59% (n = 259) were ≥65 years of age. The median serum LDH was 394 Units/L and 33.5% (n = 146) had an LDH 500 Units/L. LDH was significantly associated with ECOG-PS (p 0.001), NLR (p 0.05), mGPS (p 0.05) and 3-month survival (p 0.001). LDH was significantly associated with 3-month survival independent of weight loss (p 0.01), BMI (p 0.05), skeletal muscle mass (p 0.01), metastatic disease (p 0.05), NLR (p 0.05) and mGPS (p 0.01).LDH was associated with performance status, systemic inflammation and survival in patients with advanced cancer. LDH measurement may be considered as an aetiologic criteria and become a potential therapeutic target in the treatment of cancer cachexia.

Placostylinae are a sub-family of terrestrial land snails endemic to the southwest Pacific. Some species are harvested for food, and others are critically endangered. Here we assemble and characterise complete mitochondrial genomes, as well as three nuclear markers (partial 45S ribosomal cassettes and the histone genes H3 and H4) of five snail species from three geographical regions (New Zealand, New Caledonia and the Solomon Islands). Mitogenomes of Placostylinae snails ranged between 14,544 bp and 14,711 bp, with minor variation in the position of tRNA tyrosine (Y) and tRNA tryptophane (W). The 45S ribosomal cassette contained intra-genomic nucleotide variation in ITS2. Cassettes containing histone genes H3 and H4 and their non-transcribed spacer region were assembled for three species, with the two genes coded in the same direction. Phylogenetic analysis on this large dataset (mitochondrial genome + nuclear markers) supported geographical clustering of species but could not confidently infer monophyly of the four Placostylus species with respect to Eumecostylus cleryi. Analysis based on shorter cytochrome c oxidase sequences with a wider taxon sampling found species representing the genera Eumecostylus and Placocharis were nested within the phylogenetic diversity of Placostylus. Multi-locus phylogenetic analysis containing mitochondrial and nuclear sequences did not support monophyly of Placostylinae.

Money can be understood from an individual perspective as an abstract form of wealth. From a communal perspective, however, money is better regarded as a debt, a biophysical liability, a lien on future real income of the community. Proper recognition of this dual nature raises concerns over modern, aggressive practices of money creation. It provokes a general reassessment of current institutional agreements surrounding money. In this contribution, said agreements are shown to endow money with an unnatural power to preserve its function despite structural decay. The origin of money interest derives from such institutionally given, unnatural power, where it should be noted that interest itself leads to a strong temptation among entities with money issuance rights to issue more and more. Ultimately, considered together, the dual nature of money and the biophysical origin of money interest provoke the need for a societal reappraisal of which entities should properly be given the right to create money, and which are functioning as “legal counterfeiters”. If a transition towards a more sustainable, more equitable bioeconomy is to be realized one day, discussion over who those entities are and what their rightful role is must be reopened.

Background The limited availability of proton beam therapy (PBT) requires individual treatment selection strategies that can be based on normal tissue complication probability (NTCP) models. We developed and externally validated NTCP models for common late side-effects following PBT in brain tumour patients to optimise patients’ quality of life. Methods Cohorts from three PBT centres (216 patients) were investigated for several physician-rated endpoints at 12 and 24 months after PBT: alopecia, dry eye syndrome, fatigue, headache, hearing and memory impairment, and optic neuropathy. Dose-volume parameters of associated normal tissues and clinical factors were used for logistic regression modelling in a development cohort. Statistically significant parameters showing high area under the receiver operating characteristic curve (AUC) values in internal cross-validation were externally validated. In addition, analyses of the pooled cohorts and of time-dependent generalised estimating equations including all patient data were performed. Results In the validation study, mild alopecia was related to high dose parameters to the skin [e.g. the dose to 2% of the volume (D2%)] at 12 and 24 months after PBT. Mild hearing impairment at 24 months after PBT was associated with the mean dose to the ipsilateral cochlea. Additionally, the pooled analyses revealed dose–response relations between memory impairment and intermediate to high doses to the remaining brain as well as D2% of the hippocampi. Mild fatigue at 24 months after PBT was associated with D2% to the brainstem as well as with concurrent chemotherapy. Moreover, in generalised estimating equations analysis, dry eye syndrome was associated with the mean dose to the ipsilateral lacrimal gland. Conclusion We developed and in part validated NTCP models for several common late side-effects following PBT in brain tumour patients. Validation studies are required for further confirmation.

OBJECTIVE To evaluate surfactant protein D (SP-D) concentrations in serum and bronchoalveolar lavage fluid (BALF) from young healthy horses on pasture or housed in a typical barn. ANIMALS 20 young healthy horses. PROCEDURES Horses were randomly assigned to 1 of 2 groups (pasture, n = 10; barn, 10), and serum and BALF samples were collected for SP-D determination at baseline (all horses on pasture) and 2 weeks and 4 weeks after the barn group of horses was relocated from the pasture to the barn. Other evaluations included physical and tracheoscopic examinations. Findings were compared within and between groups. RESULTS Physical and tracheoscopic examinations, CBC, and serum biochemical analysis did not reveal evidence of respiratory disease, and no significant differences were present within and between groups. Serum SP-D concentrations did not significantly differ within and between groups, but BALF SP-D concentrations were significantly lower for the barn group at 2 weeks but not at 4 weeks, compared with baseline. The BALF SP-D concentration-to-BALF total protein concentration ratio was < 1.5 and did not significantly differ within and between groups. CONCLUSIONS AND CLINICAL RELEVANCE A mild decrease was evident in the concentration of SP-D in the BALF collected from young healthy horses after 2 weeks of exposure to a barn environment. The clinical importance of this finding remains to be determined.

PURPOSE: Stereotactic body radiation therapy (SBRT) for early stage non-small cell lung cancer (NSCLC) is a standard of care for medically inoperable patients. Our aim was to compare Common Terminology Criteria for Adverse Events (CTCAE) thoracic grade 3 or higher adverse events (AEs) of 30 Gy in one fraction (arm 1) vs. 60 Gy in 3 fractions (arm 2). METHODS: This was a randomized multi-institutional, phase II, two-arm, clinical trial. Medically inoperable patients with biopsy-proven peripheral T1/T2N0M0 NSCLC tumors were enrolled. Patients were randomized to arm 1 or arm 2 and stratified by performance status. The primary endpoint was CTCAE thoracic grade 3 or higher AEs. Secondary end points were local control (LC), progression-free survival (PFS), overall survival (OS), and quality of life (QOL). RESULTS: Between September, 2008 and April, 2015, 98 patients were randomized. Median follow-up was 53.8 months. 10 patients were lost to follow-up; 1 in arm 1 and 9 in arm 2. Thoracic grade 3 AEs were experienced by 8 (16%) patients on arm 1 and 6 (12%) patients on arm 2 there were no grade 4 or 5 AEs.. There were no differences in LC, PFS or OS (p= 0.68, 0.86 and 0.94, respectively). Arm 1 reported better social functioning (p=0.006) with less dyspnea (p=0.016) in follow-up at 6 months. CONCLUSIONS: This randomized phase II study demonstrated 30 Gy in one fraction was equivalent to 60 Gy in three fractions in terms of toxicity, LC, PFS and OS. QOL measures of social functioning and dyspnea favored single fraction SBRT.

As the world's most abundant source of terrestrial carbon, peatlands provide numerous ecosystem services, including habitat biodiversity and freshwater quality. Land and water management practices in relation to peatlands, for either exploitation or rehabilitation, are complicated by several factors: spatial diversity in geochemistry; laborious survey methods that may be subject to confounding factors; regional and irregular climate variations; a lack of generalizability regarding appropriate strategies; and, in some countries, by non-implementation of water quality assessment policies for pollution control and land use. Such factors raise uncertainty in the effectiveness of restoration and rehabilitation strategies, while modern peatland management looks to develop land use schemes that offer minimal risk to the environment. The aims of this paper were to (1) investigate the disparate factors influencing peatland management which confound appropriate interventions for enhanced water quality (2) examine how non-implementation of national policies for water pollution control may result in adverse environmental impacts, and (3) propose an innovative peatland management methodology for a detailed and robust land analysis with water quality being the primary consideration. The paper suggests that optical, radar, and radiometric remote sensing methods may be used to identify management zones within a peatland, that may require variable management strategies during restoration. Satellite remote sensing and Earth observation methodologies are well documented; hence, the prospect and properties of a less documented airborne electromagnetic approach The authors would like to thank the European Commission and the Irish Environmental Protection Agency (EPA) (Project reference number 2019-W-MS-42) for funding the collaborative international consortium (WATERPEAT) financed under the Water JPI 2018 Joint Call of the WaterWorks2017 ERA-NET Cofund. This project is funded under the EPA Research Programme 2014-2020. The EPA Research Programme is a Government of Ireland initiative funded by the Department of Communications, Climate Action and Environment. It is administered by the Environmental Protection Agency, which has the statutory function of co-ordinating and promoting environmental research. DISCLAIMER: Although every effort has been made to ensure the accuracy of the material contained in this journal paper, complete accuracy cannot be guaranteed. Neither the Environmental Protection Agency nor the authors accept any responsibility whatsoever for loss or damage occasioned or claimed to have been occasioned, in part or in full, as a consequence of any person acting or peer-reviewed

Understanding how food processing may modify allergen bioaccessibility and the evolution of immunologically active peptides in the gastrointestinal tract is essential if knowledge-based approaches to reducing the allergenicity of food are to be realised. A soy-enriched wheat-based pizza base was subjected to in vitro oral–gastro–duodenal digestion and resulting digests analysed using a combination of sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE) and mass spectrometry (MS). The digestion profile of pizza base resembled that of bread crust where higher temperatures during baking reduced protein solubility but still resulted in the generation of a complex mixture of peptides. MS profiling showed numerous peptides carrying IgE epitopes, and coeliac toxic motifs were in excess of 20–30 residues long and were only released after either 120 min of gastric digestion or a combination of gastric and duodenal digestion. In silico prediction tools showed an overestimated number of cleavage sites identified experimentally, with low levels of atypical peptic and chymotryptic cleavage sites identified particularly at glutamine residues. These data suggest that such alternative pepsin cleavage sites may play a role in digestion of glutamine-rich cereal foods. They also contribute to efforts to provide benchmarks for mapping in vitro digestion products of novel proteins which form part of the allergenicity risk assessment.

The systemic inflammatory response is associated with the loss of lean tissue, anorexia, weakness, fatigue and reduced survival in patients with advanced cancer and therefore is important in the definition of cancer cachexia. The aim of the present study was to carry out a direct comparison of the prognostic value of Eastern Cooperative Oncology Group Performance Status (ECOG-PS), modified Glasgow Prognostic Score (mGPS) and Body Mass Index/Weight Loss Grade (BMI/WL grade) in patients with advanced cancer.All data were collected prospectively across 18 sites in the UK and Ireland. Patient's age, sex, ECOG-PS, mGPS and BMI/WL grade were recorded, as were details of underlying disease including metastases. Survival data were analysed using univariate and multivariate Cox regression.A total of 730 patients were assessed. The majority of patients were male (53%), over 65 years of age (56%), had an ECOG-PS0/1 (56%), mGPS≥1 (56%), BMI≥25 (51%),2.5% weight loss (57%) and had metastatic disease (86%). On multivariate cox regression analysis ECOG-PS (HR 1.61 95%CI 1.42-1.83, p 0.001), mGPS (HR 1.53, 95%CI 1.39-1.69, p 0.001) and BMI/WL grade (HR 1.41, 95%CI 1.25-1.60, p 0.001) remained independently associated with overall survival. In patients with a BMI/WL grade 0/1 both ECOG and mGPS remained independently associated with overall survival.The ECOG/mGPS framework may form the basis of risk stratification of survival in patients with advanced cancer.

Background Weight loss (WL) and sarcopenia are associated with negative oncological outcomes including poor treatment tolerance, decreased quality of life, and reduced survival. The number of patients affected by sarcopenia and WL in Ireland and the UK is unknown. Methods A systematic review was undertaken to determine median rate of WL > 5% and computed tomography‐diagnosed sarcopenia in oncology populations. Gaps in the literature were supplemented using local data, collected as part of a 5 year prospective study. Rates of WL and sarcopenia in the population were extrapolated from these data based on incidence and prevalence of each cancer as per national cancer registries. Results We estimated that across Ireland and the UK, 128 892 cancer patients (34%) are affected by WL > 5% annually (121 641 UK; 7251 Ireland) and there are 133 707 annual cases of sarcopenia in cancer patients (35%) (126 265 UK; 7442 Ireland). Furthermore, we estimate that there are 716 124 and 771 589 cancer survivors with history of WL > 5% or sarcopenia, respectively. Conclusions Large numbers of patients are affected by cancer‐related malnutrition. Given the impact of malnutrition on oncological outcomes and long‐term frailty, there is an urgent need to improve access to cancer nutrition care.

Plasma membranes of animal cells are enriched for cholesterol. Cholesterol-dependent cytolysins (CDCs) are pore-forming toxins secreted by bacteria that target membrane cholesterol for their effector function. Phagocytes are essential for clearance of CDC-producing bacteria; however, the mechanisms by which these cells evade the deleterious effects of CDCs are largely unknown. Here, we report that interferon (IFN) signals convey resistance to CDC-induced pores on macrophages and neutrophils. We traced IFN-mediated resistance to CDCs to the rapid modulation of a specific pool of cholesterol in the plasma membrane of macrophages without changes to total cholesterol levels. Resistance to CDC-induced pore formation requires the production of the oxysterol 25-hydroxycholesterol (25HC), inhibition of cholesterol synthesis and redistribution of cholesterol to an esterified cholesterol pool. Accordingly, blocking the ability of IFN to reprogram cholesterol metabolism abrogates cellular protection and renders mice more susceptible to CDC-induced tissue damage. These studies illuminate targeted regulation of membrane cholesterol content as a host defense strategy.

Background: Optimizing quality of life (QoL) remains the central tenet of care in patients with incurable cancer; however, determinants of QoL are not clear. The objective of the current study was to examine which factors influence QoL in patients with incurable cancer. Methods: A multicenter study of adult patients with advanced cancer was conducted in Ireland and the United Kingdom between 2011 and 2016. Data were collected from patients at study entry and included patient demographics, Eastern Cooperative Oncology Group performance status (ECOG‐PS), nutritional parameters (the percentage weight loss [%WL]), muscle parameters assessed using computed tomography images (skeletal muscle index and skeletal muscle attenuation), inflammatory markers (modified Glasgow Prognostic score [mGPS]), and QoL data (the European Organization for Research and Treatment Quality‐of‐Life Questionnaire C‐30). The relation between clinical, nutritional, and inflammatory parameters with QoL was assessed using the Spearman rank correlation coefficient and multivariate binary logistic regression. Components of the European Organization for Research and Treatment Quality‐of‐Life Questionnaire C‐30 (physical function, fatigue, and appetite loss) and summary QoL scores were mean‐dichotomized for the logistic regression analyses. Results: Data were available for 1027 patients (51% men; median age, 66 years). Gastrointestinal cancer was most prevalent (40%), followed by lung cancer (26%) and breast cancer (9%). Distant metastatic disease was present in 87% of patients. The %WL, ECOG‐PS, and mGPS were significantly correlated with deteriorating QoL functional and symptom scales (all P < .001). On multivariate regression analysis, >10% WL (odds ratio [OR], 2.69; 95% CI, 1.63‐4.42), an ECOG‐PS of 3 or 4 (OR, 14.33; 95% CI, 6.76‐30.37), and an mGPS of 2 (OR, 1.58; 95% CI, 1.09‐2.29) were independently associated with poorer summary QoL scores. These parameters were also independently associated with poorer physical function, fatigue, and appetite loss (all P < .05). Low skeletal muscle attenuation was independently associated with poorer physical functioning (OR, 1.67; 95% CI, 1.09‐2.56), but muscle parameters were not independently associated with fatigue, appetite loss, or QoL summary scores. Conclusions: The current findings indicate that QoL is determined (at least in part) by WL, ECOG‐PS, and the systemic inflammatory response in patients with advanced cancer. Identifying early predictors of poor QoL may allow the identification of patients who may benefit from early referral to palliative and supportive care, which has been shown to improve QoL.

PURPOSE To provide evidence-based recommendations to practicing clinicians on radiographic imaging and biomarker surveillance strategies after definitive curative-intent therapy in patients with stage I-III non–small-cell lung cancer (NSCLC) and SCLC. METHODS ASCO convened an Expert Panel of medical oncology, thoracic surgery, radiation oncology, pulmonary, radiology, primary care, and advocacy experts to conduct a literature search, which included systematic reviews, meta-analyses, randomized controlled trials, and prospective and retrospective comparative observational studies published from 2000 through 2019. Outcomes of interest included survival, disease-free or recurrence-free survival, and quality of life. Expert Panel members used available evidence and informal consensus to develop evidence-based guideline recommendations. RESULTS The literature search identified 14 relevant studies to inform the evidence base for this guideline. RECOMMENDATIONS Patients should undergo surveillance imaging for recurrence every 6 months for 2 years and then annually for detection of new primary lung cancers. Chest computed tomography imaging is the optimal imaging modality for surveillance. Fluorodeoxyglucose positron emission tomography/computed tomography imaging should not be used as a surveillance tool. Surveillance imaging may not be offered to patients who are clinically unsuitable for or unwilling to accept further treatment. Age should not preclude surveillance imaging. Circulating biomarkers should not be used as a surveillance strategy for detection of recurrence. Brain magnetic resonance imaging should not be used for routine surveillance in stage I-III NSCLC but may be used every 3 months for the first year and every 6 months for the second year in patients with stage I-III small-cell lung cancer who have undergone curative-intent treatment.

Author(s): Yuan, Zilong; Rong, Yi; Benedict, Stanley H; Daly, Megan E; Qiu, Jianfeng; Yamamoto, Tokihiro | Abstract: PURPOSE:Adaptive radiotherapy (ART) has potential to reduce toxicity and facilitate safe dose escalation. Dose calculations with the planning CT deformed to cone beam CT (CBCT) have shown promise for estimating the "dose of the day". The purpose of this study is to investigate the "dose of the day" calculation accuracy based on CBCT and deformable image registration (DIR) for lung cancer radiotherapy. METHODS:A total of 12 lung cancer patients were identified, for which daily CBCT imaging was performed for treatment positioning. A re-planning CT (rCT) was acquired after 20nGy for all patients. A virtual CT (vCT) was created by deforming initial planning CT (pCT) to the simulated CBCT that was generated from deforming CBCT to rCT acquired on the same day. Treatment beams from the initial plan were copied to the vCT and rCT for dose calculation. Dosimetric agreement between vCT-based and rCT-based accumulated doses was evaluated using the Bland-Altman analysis. RESULTS:Mean differences in dose-volume metrics between vCT and rCT were smaller than 1.5%, and most discrepancies fell within the range ofn±n5% for the target volume, lung, esophagus, and heart. For spinal cord Dmax , a large mean difference of -5.55% was observed, which was largely attributed to very limited CBCT image quality (e.g., truncation artifacts). CONCLUSION:This study demonstrated a reasonable agreement in dose-volume metrics between dose accumulation based on vCT and rCT, with the exception for cases with poor CBCT image quality. These findings suggest potential utility of vCT for providing a reasonable estimate of the "dose of the day", and thus facilitating the process of ART for lung cancer.

Lung cancer is the leading cause of death in both men and women in the United States (1). With increasing implementation of low dose computed tomography (CT) screening in high-risk populations, more patients should be diagnosed with early stage disease in the coming years, amenable to curative intent therapy (2). However, no firm consensus yet guides the frequency and modality of surveillance imaging following definitive treatment, with variable guidelines from large national and international oncologic societies.

PURPOSE To provide evidence-based recommendations to practicing clinicians on management of patients with stage III non–small-cell lung cancer (NSCLC). METHODS An Expert Panel of medical oncology, thoracic surgery, radiation oncology, pulmonary oncology, community oncology, research methodology, and advocacy experts was convened to conduct a literature search, which included systematic reviews, meta-analyses, and randomized controlled trials published from 1990 through 2021. Outcomes of interest included survival, disease-free or recurrence-free survival, and quality of life. Expert Panel members used available evidence and informal consensus to develop evidence-based guideline recommendations. RESULTS The literature search identified 127 relevant studies to inform the evidence base for this guideline. RECOMMENDATIONS Evidence-based recommendations were developed to address evaluation and staging workup of patients with suspected stage III NSCLC, surgical management, neoadjuvant and adjuvant approaches, and management of patients with unresectable stage III NSCLC. Additional information is available at www.asco.org/thoracic-cancer-guidelines .

Purpose: To compare the dosimetric differences in stereotactic radiosurgery between use of passively scattered protons (PSRS) versus photons (XSRS) for pituitary adenomas. Methods and Materials: Nine patients with pituitary adenomas were selected among patients receiving single-fraction proton stereotactic radiosurgery (PSRS) between 2016 and 2017. These cases were replanned with XSRS using volumetric-modulated arc therapy with 2.5 mm and 5 mm multileaf collimators (2.5XSRS and 5XSRS, respectively). PSRS was planned with a dedicated single scattering stereotactic proton unit delivered via 3 equally or unequally weighted isocentric fields. XSRS plans were created with optimization to spare organs at risk. Plans were generated using the original total treatment dose delivered in 1 fraction. Results: Plans were evaluated for target volume dosimetry and estimated clinical toxicity. There was no significant difference in clinical target volume V100%, V95%, V90% or homogeneity index between treatment modalities. PSRS offered lower maximum dose (Dmax) to organs at risk and equivalent uniform dose (EUD) compared with 5XSRS and 2.5XSRS, respectively, for critical structures including optic nerve (right, Dmax 4.18, 5.32, 5.41; EUD 3.35, 4.08, 4.20) and hypothalamus (Dmax 1.71, 3.94, 3.77; EUD 0.94, 2.47, 2.39; P < .05 for PSRS vs 5XSRS and 2.5XSRS). The projected risk of secondary tumors in excess of baseline was lowest for PSRS plans (PSRS 5.28, 5XSRS 12.93, 2.5XSRS 12.66 cases per 10,000 patient-years; P = .008 for PSRS vs 5XSRS, PSRS vs 2.5XSRS, and P = .77 for 5XSRS vs 2.5XSRS). Conclusions: We demonstrate that neither modality has empirically superior dosimetry and identify potential clinical advantages as well as limitations of each technique. PSRS, 5XSRS and 2.5XSRS demonstrate comparable target volume dosimetry for pituitary adenoma. PSRS compared with XSRS modalities offers modestly decreased maximum dose and EUD to critical proximal structures and decreases risk of radiation-induced secondary tumors by more than half.

Medical students have lost invaluable exposure to surgery and research during the COVID-19 pandemic, with the majority of placements being cancelled or converted online 1. As such, they have been denied opportunities and mentorship which have historically influenced a surgical and/or clinical-academic career 2-3.

Modern short-range gravity experiments that seek to test the Newtonian inverse-square law or weak equivalence principle of general relativity typically involve measuring the minute variations in the twist angle of a torsion pendulum. Motivated by various theoretical arguments, recent efforts largely focus on measurements with test mass separations in the sub-millimeter regime. To measure the twist, many experiments employ an optical autocollimator with a noise performance of ∼300 nrad[Formula: see text] in the 0.1–10 mHz band, enabling a measurement uncertainty of a few nanoradians in a typical integration time. We investigated an alternative method for measuring a small twist angle through the construction of a modified Michelson interferometer. The main modification is the introduction of two additional arms that allow for improved angular alignment. A series of detectors and LabView software routines were developed to determine the orientation of a mirror attached to a sinusoidally driven rotation stage that oscillated with an amplitude of 0.35 mrad and a period of 200 s. In these measurements, the resolution of the interferometer is 8.1 μrad per fringe, while its dynamic range spanned 0.962 mrad. We compare the performance of this interferometric optical system to existing autocollimator-based methods, discussing its implementation, possible advantages, and future potential, as well as disadvantages and limitations.

Germline defects affecting the DNA-binding domain of the transcription factor FLI1 are associated with a bleeding disorder that is characterized by the presence of large, fused α-granules in platelets. We investigated whether the genes showing abnormal expression in FLI1-deficient platelets could be involved in platelet α-granule biogenesis by undertaking transcriptome analysis of control platelets and platelets harboring a DNA-binding variant of FLI1. Our analysis identified 2,276 transcripts that were differentially expressed in FLI1-deficient platelets. Functional annotation clustering of the coding transcripts revealed significant enrichment for gene annotations relating to protein transport, and identified Sorting nexin 24 (SNX24) as a candidate for further investigation. Using an induced pluripotent stem cell-derived megakaryocyte model, SNX24 expression was found to be increased during the early stages of megakaryocyte differentiation and downregulated during proplatelet formation, indicating tight regulatory control during megakaryopoiesis. CRISPR-Cas9 mediated knockout (KO) of SNX24 led to decreased expression of immature megakaryocyte markers, CD41 and CD61, and increased expression of the mature megakaryocyte marker CD42b (P=0.0001), without affecting megakaryocyte polyploidisation, or proplatelet formation. Electron microscopic analysis revealed an increase in empty membrane-bound organelles in SNX24 KO megakaryocytes, a reduction in α-granules and an absence of immature and mature multivesicular bodies, consistent with a defect in the intermediate stage of α-granule maturation. Co-localization studies showed that SNX24 associates with each compartment of α-granule maturation. Reduced expression of CD62P and VWF was observed in SNX24 KO megakaryocytes. We conclude that SNX24 is required for α-granule biogenesis and intracellular trafficking of α-granule cargo within megakaryocytes.