Assessing Oral Intake Outcomes in Head and Neck Cancer Patients Treated with Definitive Radiation with or Without Chemotherapy

Background: Head and neck cancer treatment modalities can significantly impact functional outcomes of patients, especially oral intake (Brizel, et al N Engl J Med 1998; Kamal, et al Support Care Cancer 2019). Radiation therapy in particular has been associated with posttreatment xerostomia and dysphagia (Adelstein, et al J Clin Oncol 2003; Hutcheson, et al Cancer 2013) which can affect quality of life and impair weight gain, contributing to worse long-term outcomes (Payakachat, et al Head Neck, 2013). Early speech-language pathology intervention has shown to be effective in improving these functional outcomes in this population (Greco, et al Int J Radiat Oncol Biol Phys 2018). Objectives: The purpose of this study is to evaluate oral intake outcomes of patients undergoing definitive radiation therapy with or without chemotherapy for head and neck squamous cell carcinoma. Methods: A cohort of patients with stage III or IV squamous cell carcinoma of the oropharynx, larynx, and hypopharynx treated with definitive radiation therapy with or without chemotherapy were extracted from system database. Patients with evidence of distant metastases were excluded. Swallow function was assessed both pre- and post-treatment (within four months of treatment initiation or conclusion) with the Functional Oral Intake Scale (FOIS) (Crary et al, Arch Phys Med Rehabil, 2005) as measured by a Speech-Language Pathologist (SLP) involved in the patient\u27s care. Body mass index (BMI) was evaluated within four months of treatment initiation and one year after treatment completion. The use of enteral feeding at one-year post-treatment was also assessed. Data was analyzed with descriptive statistical methods, Wilcoxon sign rank tests, and [chi]2d tests. Results: The sample included 152 patients. Table 1 highlights patient baseline characteristics, tumor location, and treatment. FOIS scores decreased from pre-treatment to post-treatment, with 75% of patients having a FOIS of 7 at pre-treatment compared with only 13.8% at the post-treatment time point (Table 1). Median BMI also decreased from pre-treatment to one-year post-treatment (Table 2). At one-year post-treatment, 23.7% patients (n=33) required enteral feeding. Conclusions: Definitive radiation therapy with or without chemotherapy in the treatment of head and neck cancer is associated with impaired oral intake. Treatment is also associated with decreases in BMI and longer use of enteral feeding, which may reflect sequelae of impaired oral intake. These factors have a negative impact on quality of life and can lead to long-term morbidity. Integrative treatment plans would therefore benefit from speech-language pathology interventions throughout the treatment process

Assessing Oral Intake Outcomes in Head and Neck Cancer Patients Treated with Definitive Radiation with or Without Chemotherapy

Background: Head and neck cancer treatment modalities can significantly impact functional outcomes of patients, especially oral intake (Brizel, et al N Engl J Med 1998; Kamal, et al Support Care Cancer 2019). Radiation therapy in particular has been associated with posttreatment xerostomia and dysphagia (Adelstein, et al J Clin Oncol 2003; Hutcheson, et al Cancer 2013) which can affect quality of life and impair weight gain, contributing to worse long-term outcomes (Payakachat, et al Head Neck, 2013). Early speech-language pathology intervention has shown to be effective in improving these functional outcomes in this population (Greco, et al Int J Radiat Oncol Biol Phys 2018). Objectives: The purpose of this study is to evaluate oral intake outcomes of patients undergoing definitive radiation therapy with or without chemotherapy for head and neck squamous cell carcinoma. Methods: A cohort of patients with stage III or IV squamous cell carcinoma of the oropharynx, larynx, and hypopharynx treated with definitive radiation therapy with or without chemotherapy were extracted from system database. Patients with evidence of distant metastases were excluded. Swallow function was assessed both pre- and post-treatment (within four months of treatment initiation or conclusion) with the Functional Oral Intake Scale (FOIS) (Crary et al, Arch Phys Med Rehabil, 2005) as measured by a Speech-Language Pathologist (SLP) involved in the patient\u27s care. Body mass index (BMI) was evaluated within four months of treatment initiation and one year after treatment completion. The use of enteral feeding at one-year post-treatment was also assessed. Data was analyzed with descriptive statistical methods, Wilcoxon sign rank tests, and [chi]2d tests. Results: The sample included 152 patients. Table 1 highlights patient baseline characteristics, tumor location, and treatment. FOIS scores decreased from pre-treatment to post-treatment, with 75% of patients having a FOIS of 7 at pre-treatment compared with only 13.8% at the post-treatment time point (Table 1). Median BMI also decreased from pre-treatment to one-year post-treatment (Table 2). At one-year post-treatment, 23.7% patients (n=33) required enteral feeding. Conclusions: Definitive radiation therapy with or without chemotherapy in the treatment of head and neck cancer is associated with impaired oral intake. Treatment is also associated with decreases in BMI and longer use of enteral feeding, which may reflect sequelae of impaired oral intake. These factors have a negative impact on quality of life and can lead to long-term morbidity. Integrative treatment plans would therefore benefit from speech-language pathology interventions throughout the treatment process

Validation of clinical acceptability of deep-learning-based automated segmentation of organs-at-risk for head-and-neck radiotherapy treatment planning

IntroductionOrgan-at-risk segmentation for head and neck cancer radiation therapy is a complex and time-consuming process (requiring up to 42 individual structure, and may delay start of treatment or even limit access to function-preserving care. Feasibility of using a deep learning (DL) based autosegmentation model to reduce contouring time without compromising contour accuracy is assessed through a blinded randomized trial of radiation oncologists (ROs) using retrospective, de-identified patient data.MethodsTwo head and neck expert ROs used dedicated time to create gold standard (GS) contours on computed tomography (CT) images. 445 CTs were used to train a custom 3D U-Net DL model covering 42 organs-at-risk, with an additional 20 CTs were held out for the randomized trial. For each held-out patient dataset, one of the eight participant ROs was randomly allocated to review and revise the contours produced by the DL model, while another reviewed contours produced by a medical dosimetry assistant (MDA), both blinded to their origin. Time required for MDAs and ROs to contour was recorded, and the unrevised DL contours, as well as the RO-revised contours by the MDAs and DL model were compared to the GS for that patient.ResultsMean time for initial MDA contouring was 2.3 hours (range 1.6-3.8 hours) and RO-revision took 1.1 hours (range, 0.4-4.4 hours), compared to 0.7 hours (range 0.1-2.0 hours) for the RO-revisions to DL contours. Total time reduced by 76% (95%-Confidence Interval: 65%-88%) and RO-revision time reduced by 35% (95%-CI,-39%-91%). All geometric and dosimetric metrics computed, agreement with GS was equivalent or significantly greater (p<0.05) for RO-revised DL contours compared to the RO-revised MDA contours, including volumetric Dice similarity coefficient (VDSC), surface DSC, added path length, and the 95%-Hausdorff distance. 32 OARs (76%) had mean VDSC greater than 0.8 for the RO-revised DL contours, compared to 20 (48%) for RO-revised MDA contours, and 34 (81%) for the unrevised DL OARs.ConclusionDL autosegmentation demonstrated significant time-savings for organ-at-risk contouring while improving agreement with the institutional GS, indicating comparable accuracy of DL model. Integration into the clinical practice with a prospective evaluation is currently underway

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk.

Blood pressure is a heritable trait influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (≥140 mm Hg systolic blood pressure or  ≥90 mm Hg diastolic blood pressure). Even small increments in blood pressure are associated with an increased risk of cardiovascular events. This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

The genetic architecture of the human cerebral cortex

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder

Defining the causes of sporadic Parkinson's disease in the global Parkinson's genetics program (GP2)

The Global Parkinson’s Genetics Program (GP2) will genotype over 150,000 participants from around the world, and integrate genetic and clinical data for use in large-scale analyses to dramatically expand our understanding of the genetic architecture of PD. This report details the workflow for cohort integration into the complex arm of GP2, and together with our outline of the monogenic hub in a companion paper, provides a generalizable blueprint for establishing large scale collaborative research consortia

Multi-ancestry genome-wide association meta-analysis of Parkinson?s disease

Although over 90 independent risk variants have been identified for Parkinson’s disease using genome-wide association studies, most studies have been performed in just one population at a time. Here we performed a large-scale multi-ancestry meta-analysis of Parkinson’s disease with 49,049 cases, 18,785 proxy cases and 2,458,063 controls including individuals of European, East Asian, Latin American and African ancestry. In a meta-analysis, we identified 78 independent genome-wide significant loci, including 12 potentially novel loci (MTF2, PIK3CA, ADD1, SYBU, IRS2, USP8, PIGL, FASN, MYLK2, USP25, EP300 and PPP6R2) and fine-mapped 6 putative causal variants at 6 known PD loci. By combining our results with publicly available eQTL data, we identified 25 putative risk genes in these novel loci whose expression is associated with PD risk. This work lays the groundwork for future efforts aimed at identifying PD loci in non-European populations

Multiorgan MRI findings after hospitalisation with COVID-19 in the UK (C-MORE): a prospective, multicentre, observational cohort study

Introduction: The multiorgan impact of moderate to severe coronavirus infections in the post-acute phase is still poorly understood. We aimed to evaluate the excess burden of multiorgan abnormalities after hospitalisation with COVID-19, evaluate their determinants, and explore associations with patient-related outcome measures. Methods: In a prospective, UK-wide, multicentre MRI follow-up study (C-MORE), adults (aged ≥18 years) discharged from hospital following COVID-19 who were included in Tier 2 of the Post-hospitalisation COVID-19 study (PHOSP-COVID) and contemporary controls with no evidence of previous COVID-19 (SARS-CoV-2 nucleocapsid antibody negative) underwent multiorgan MRI (lungs, heart, brain, liver, and kidneys) with quantitative and qualitative assessment of images and clinical adjudication when relevant. Individuals with end-stage renal failure or contraindications to MRI were excluded. Participants also underwent detailed recording of symptoms, and physiological and biochemical tests. The primary outcome was the excess burden of multiorgan abnormalities (two or more organs) relative to controls, with further adjustments for potential confounders. The C-MORE study is ongoing and is registered with ClinicalTrials.gov, NCT04510025. Findings: Of 2710 participants in Tier 2 of PHOSP-COVID, 531 were recruited across 13 UK-wide C-MORE sites. After exclusions, 259 C-MORE patients (mean age 57 years [SD 12]; 158 [61%] male and 101 [39%] female) who were discharged from hospital with PCR-confirmed or clinically diagnosed COVID-19 between March 1, 2020, and Nov 1, 2021, and 52 non-COVID-19 controls from the community (mean age 49 years [SD 14]; 30 [58%] male and 22 [42%] female) were included in the analysis. Patients were assessed at a median of 5·0 months (IQR 4·2–6·3) after hospital discharge. Compared with non-COVID-19 controls, patients were older, living with more obesity, and had more comorbidities. Multiorgan abnormalities on MRI were more frequent in patients than in controls (157 [61%] of 259 vs 14 [27%] of 52; p&lt;0·0001) and independently associated with COVID-19 status (odds ratio [OR] 2·9 [95% CI 1·5–5·8]; padjusted=0·0023) after adjusting for relevant confounders. Compared with controls, patients were more likely to have MRI evidence of lung abnormalities (p=0·0001; parenchymal abnormalities), brain abnormalities (p&lt;0·0001; more white matter hyperintensities and regional brain volume reduction), and kidney abnormalities (p=0·014; lower medullary T1 and loss of corticomedullary differentiation), whereas cardiac and liver MRI abnormalities were similar between patients and controls. Patients with multiorgan abnormalities were older (difference in mean age 7 years [95% CI 4–10]; mean age of 59·8 years [SD 11·7] with multiorgan abnormalities vs mean age of 52·8 years [11·9] without multiorgan abnormalities; p&lt;0·0001), more likely to have three or more comorbidities (OR 2·47 [1·32–4·82]; padjusted=0·0059), and more likely to have a more severe acute infection (acute CRP &gt;5mg/L, OR 3·55 [1·23–11·88]; padjusted=0·025) than those without multiorgan abnormalities. Presence of lung MRI abnormalities was associated with a two-fold higher risk of chest tightness, and multiorgan MRI abnormalities were associated with severe and very severe persistent physical and mental health impairment (PHOSP-COVID symptom clusters) after hospitalisation. Interpretation: After hospitalisation for COVID-19, people are at risk of multiorgan abnormalities in the medium term. Our findings emphasise the need for proactive multidisciplinary care pathways, with the potential for imaging to guide surveillance frequency and therapeutic stratification