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PURPOSE: Paleolithic Diet Fraction (PDF) estimates how large a portion of the absolute dietary intake stems from food groups included in the Paleolithic diet. In randomized controlled trials higher PDFs have been associated with healthier levels of cardiometabolic risk markers. Our aim was to build upon these findings by examining associations between PDF and mortality and incidence of cardiometabolic disease in the prospective Malmö Diet and Cancer Study. METHODS: PDF was calculated from an interview-based, modified diet history method, and associations were estimated by using multivariable Cox proportional hazards regression. The examined cohort consisted of 24,104 individuals (44-74 years, 63% women) without previous coronary events, diabetes, or stroke at baseline (1992-1996). A total of 10,092 individuals died during a median follow-up of 18 years. RESULTS: Median PDF was 40% (0-90%). The adjusted hazard ratios (HR) for PDF as a continuous variable (from 0 to 100%) were for risk of death from all causes 0.55 [95% CI 0.45, 0.66], tumor 0.68 [95% CI 0.49, 0.93], cardiovascular 0.55 [95% CI 0.39, 0.78], respiratory 0.44 [95% CI 0.21, 0.90], neurological 0.26 [95% CI 0.11, 0.60], digestive, 0.10 [95% CI 0.03, 0.30], and other diseases 0.64 [95% CI 0.41, 1.00]. The corresponding HR for risk of coronary event was 0.61 [95% 0.43, 0.86], for ischemic stroke it was 0.73 [95% 0.48, 1.09] and for type 2 diabetes it was 0.82 [95% 0.61, 1.10]. CONCLUSION: Observational data suggest an inverse association between PDF and all-cause as well as cause-specific mortality and incidence of cardiometabolic disease.

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Background: Osteosarcoma is most prevalently found primary malignant bone tumors, with primary metastatic patients accounting for approximately 25% of all osteosarcoma patients, yet their 5-year OS remains below 30%. Bilirubin plays a key role in oxidative stress-associated events, including malignancies, making the regulation of its serum levels a potential anti-tumor strategy. Herein, we investigated the association of osteosarcoma prognosis with serum levels of TBIL, IBIL and DBIL, and further explored the mechanisms by which bilirubin affects tumor invasion and migration. Methods: ROC curve was plotted to assess survival conditions based on the determined optimal cut-off values and the AUC. Then, Kaplan-Meier curves, along with Cox proportional hazards model, was applied for survival analysis. Inhibitory function of IBIL on the malignant properties of osteosarcoma cells was examined using the qRT-PCR, transwell assays, western blotting, and flow cytometry. Results: We found that, versus osteosarcoma patients with pre-operative higher IBIL (>8.9 µmol/L), those with low IBIL (≤8.9 µmol/L) had shorter OS and PFS. As indicated by the Cox proportional hazards model, pre-operative IBIL functioned as an independent prognostic factor for OS and PFS in total and gender-stratified osteosarcoma patients (P < 0.05 for all). In vitro experiments further confirmed that IBIL inhibits PI3K/AKT phosphorylation and downregulates MMP-2 expression via reducing intracellular ROS, thereby decreasing the invasion of osteosarcoma cells. Conclusions: IBIL may serve as an independent prognostic predictor for osteosarcoma patients. IBIL impairs invasion of osteosarcoma cells through repressing the PI3K/AKT/MMP-2 pathway by suppressing intracellular ROS, thus inhibiting its metastatic potential.

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Purpose: To evaluate associations between rare dysfunctional complement factor I (CFI) genetic variant status and progression to advanced age-related macular degeneration (AAMD), geographic atrophy (GA), and neovascular disease (NV). Design: Prospective, longitudinal study. Participants: Patients aged 55 to 80 years at baseline identifying as White with non-AAMD in 1 or both eyes at baseline were included. Follow-up grades were assigned as early, intermediate, or AAMD (GA or NV). CFI variants were categorized using genotyping and sequencing platforms. Methods: Analyses were performed using the Seddon Longitudinal Cohort Study (N = 2116 subjects, 3901 eyes, and mean follow-up of 8.3 years) and the Age-Related Eye Disease Study (N = 2837 subjects, 5200 eyes, and mean follow-up of 9.2 years). CFI rare variants associated with low serum factor I (FI) protein levels and decreased FI function (type 1), other AMD genetic variants, and demographic, behavioral, and ocular factors were evaluated. Generalized estimating equations methods were used to assess the association between CFI rare variants and progression, independent of other genetic variants and covariates. Main Outcome Measures: Progression to AAMD, GA, or NV. Results: In the prospective cohort of 4953 subjects (9101 eyes with non-AAMD at baseline), 1% were type 1 rare CFI carriers. Over 12 years, progression to AAMD was 44% for carriers and 20% for noncarriers (P < 0.001), 30% of carriers versus 10% of noncarriers progressed to GA (P < 0.001), and 18% of carriers compared with 11% of noncarriers progressed to NV (P = 0.049). CFI carriers were more likely to have a family history of AMD (P for trend = 0.035) and a higher baseline AMD grade (P < 0.001). After adjusting for all covariates, CFI carrier status was associated with progression to GA (odds ratio [OR] = 1.91; 95% confidence interval [CI] = 1.03, 3.52) but not NV (OR = 0.96). Higher body mass index was associated with progression among CFI carriers (body mass index ≥ 25 vs. < 25; OR = 5.8; 95% CI 1.5, 22.3) but not for noncarriers (OR = 1.1; 95% CI = 0.9, 1.3), with P_interaction = 0.011. Conclusions: Results suggest that carriers of rare dysfunctional type 1 CFI variants are at higher risk for progression to AAMD with GA. Financial Disclosures: Proprietary or commercial disclosure may be found after the references.

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Primary bone cancer (PBC) comprises several subtypes each underpinned by distinctive genetic drivers. This driver diversity produces novel morphological features and clinical behaviour that serendipitously makes PBC an excellent metastasis model. Here, we report that some transfer RNA-derived small RNAs termed tRNA fragments (tRFs) perform as a constitutive tumour suppressor mechanism by blunting a potential pro-metastatic protein-RNA interaction. This mechanism is reduced in PBC progression with a gradual loss of tRNAGlyTCC cleavage into 5' end tRF-GlyTCC when comparing low-grade, intermediate-grade and high-grade patient tumours. We detected recurrent activation of miR-140 leading to upregulated RUNX2 expression in high-grade patient tumours. Both tRF-GlyTCC and RUNX2 share a sequence motif in their 3' ends that matches the YBX1 recognition site known to stabilise pro-metastatic mRNAs. Investigating some aspects of this interaction network, gain- and loss-of-function experiments using small RNA mimics and antisense LNAs, respectively, showed that ectopic tRF-GlyTCC reduced RUNX2 expression and dispersed 3D micromass architecture in vitro. iCLIP sequencing revealed YBX1 physical binding to the 3' UTR of RUNX2. The interaction between YBX1, tRF-GlyTCC and RUNX2 led to the development of the RUNX2 inhibitor CADD522 as a PBC treatment. CADD522 assessment in vitro revealed significant effects on PBC cell behaviour. In xenograft mouse models, CADD522 as a single agent without surgery significantly reduced tumour volume, increased overall and metastasis-free survival and reduced cancer-induced bone disease. Our results provide insight into PBC molecular abnormalities that have led to the identification of new targets and a new therapeutic.

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Background & Aims: The aim of the study was to evaluate the efficacy and safety of adjuvant sorafenib treatment compared with placebo in patients with hepatocellular carcinoma who underwent local ablation. Methods: The SORAMIC trial is a randomised controlled trial with diagnostic, local ablation, and palliative sub-study arms. After initial imaging within the diagnostic study, patients were assigned to local ablation or palliative arms. In the local ablation cohort, patients were randomised 1:1 to local ablation + sorafenib vs. local ablation + placebo. The primary endpoint was time-to-recurrence (TTR). Secondary endpoints were local control rate and safety in terms of adverse events and quality-of-life. Results: The recruitment was terminated prematurely after 104 patients owing to slow recruitment. One patient was excluded because of a technical failure. Fifty-four patients were randomised to local ablation + sorafenib and 49 to local ablation + placebo. Eighty-eight patients who underwent standardised follow-up imaging comprised the per-protocol population. The median TTR was 15.2 months in the sorafenib arm and 16.4 months in the placebo arm (hazard ratio 1.1; 95% CI 0.53-2.2; p = 0.82). Out of 136 lesions ablated within the trial, there was no difference in local recurrence rate between sorafenib (6/69, 8.6%) and placebo groups (5/67, 5.9%; p = 0.792).Overall (92.5% vs. 71.4%, p = 0.008) and drug-related (81.4% vs. 55.1%, p = 0.003) adverse events were more common in the sorafenib arm compared with the placebo arm. Dose reduction because of adverse events were common in the sorafenib arm (79.6% vs. 30.6%, p <0.001). Conclusions: Adjuvant sorafenib did not improve in TTR or local control rate after local ablation in patients with hepatocellular carcinoma within the limitations of an early terminated trial. Impact and implications: Local ablation is the standard of care treatment in patients with early stages of hepatocellular carcinoma, along with surgical therapies. However, there is a risk of disease recurrence during follow-up. Sorafenib, an oral medication, is a routinely used treatment for patients with advanced hepatocellular carcinoma. This study found that sorafenib treatment after local ablation in people with early hepatocellular carcinoma did not significantly improve the disease-free period compared with placebo. Clinical trial number: EudraCT 2009-012576-27, NCT01126645.

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Background & Aims: Transcatheter arterial chemoembolisation (TACE) is recommended for patients with hepatocellular carcinoma devoid of macrovascular invasion or extrahepatic spread but not eligible for curative therapies. We compared the efficacy and safety of the combination of a single TACE and external conformal radiotherapy (CRT) vs. classical TACE. Methods: TACERTE was an open-labelled, randomised controlled trial with a 1:1 allocation rate to two or three TACE (arm A) or one TACE + CRT (arm B). Participants had a mean age of 70 years, and 86% were male. The aetiology was alcohol in 85%. The primary endpoint was liver progression-free survival (PFS) in the intention-to-treat population. The typical CRT schedule was 54 Gy in 18 sessions of 3 Gy. Results: Of the 120 participants randomised, 64 were in arm A and 56 in arm B; 100 participants underwent the planned schedule and defined the 'per-protocol' group. In intention-to-treat participants, the liver PFS at 12 and 18 months were 59% and 19% in arm A and 61% and 36% in arm B (hazard ratio [HR] 0.69; 95% CI 0.40-1.18; p = 0.17), respectively. In the per-protocol population, treated liver PFS tended to be better in arm B (HR 0.61; 95% CI 0.34-1.06; p = 0.081) than in arm A. Liver-related grade III-IV adverse events were more frequent in arm B than in arm A. Median overall survival reached 30 months (95% CI 23-35) in arm A and 22 months (95% CI 15.7-26.2) in arm B. Conclusions: Although TACE + CRT tended to improve local control, this first Western randomised controlled trial showed that the combined strategy failed to increase PFS or overall survival and led more frequently to liver-related adverse effects. Impact and implications: Hepatocellular carcinoma is frequently treated by arterial embolisation of the tumour and more recently by external radiotherapy. We tried to determine whether combination of the two treatments (irradiation after embolisation) might produce interesting results. Our results in this prospective randomised study were not able to demonstrate a beneficial effect of combining embolisation and irradiation in these patients. On the contrary, we observed more adverse effects with the combined treatment. Clinical Trials Registration: NCT01300143.

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Background & Aims: The prevalence and aetiology of liver fibrosis vary over time and impact racial/ethnic groups unevenly. This study measured time trends and identified factors associated with advanced liver fibrosis in the United States. Methods: Standardised methods were used to analyse data on 47,422 participants (≥20 years old) in the National Health and Nutrition Examination Survey (1999-2018). Advanced liver fibrosis was defined as Fibrosis-4 ≥2.67 and/or Forns index ≥6.9 and elevated alanine aminotransferase. Results: The estimated number of people with advanced liver fibrosis increased from 1.3 million (95% CI 0.8-1.9) to 3.5 million (95% CI 2.8-4.2), a nearly threefold increase. Prevalence was higher in non-Hispanic Black and Mexican American persons than in non-Hispanic White persons. In multivariable logistic regression analysis, cadmium was an independent risk factor in all racial/ethnic groups. Smoking and current excessive alcohol use were risk factors in most. Importantly, compared with non-Hispanic White persons, non-Hispanic Black persons had a distinctive set of risk factors that included poverty (odds ratio [OR] 2.09; 95% CI 1.44-3.03) and susceptibility to lead exposure (OR 3.25; 95% CI 1.95-5.43) but did not include diabetes (OR 0.88; 95% CI 0.61-1.27; p =0.52). Non-Hispanic Black persons were more likely to have high exposure to lead, cadmium, polychlorinated biphenyls, and poverty than non-Hispanic White persons. Conclusions: The number of people with advanced liver fibrosis has increased, creating a need to expand the liver care workforce. The risk factors for advanced fibrosis vary by race/ethnicity. These differences provide useful information for designing screening programmes. Poverty and toxic exposures were associated with the high prevalence of advanced liver fibrosis in non-Hispanic Black persons and need to be addressed. Impact and Implications: Because liver disease often produces few warning signs, simple and inexpensive screening tests that can be performed by non-specialists are needed to allow timely diagnosis and linkage to care. This study shows that non-Hispanic Black persons have a distinctive set of risk factors that need to be taken into account when designing liver disease screening programs. Exposure to exogenous toxins may be especially important risk factors for advanced liver fibrosis in non-Hispanic Black persons.

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Cancer-associated fibroblasts (CAFs) can exert their immunosuppressive effects by secreting various effectors that are involved in the regulation of tumor-infiltrating immune cells as well as other immune components in the tumor immune microenvironment (TIME), thereby promoting tumorigenesis, progression, metastasis, and drug resistance. Although a large number of studies suggest that CAFs play a key regulatory role in the development of head and neck squamous cell carcinoma (HNSCC), there are limited studies on the relevance of CAFs to the prognosis of HNSCC. In this study, we identified a prognostic signature containing eight CAF-related genes for HNSCC by univariate Cox analysis, lasso regression, stepwise regression, and multivariate Cox analysis. Our validation in primary cultures of CAFs from human HNSCC and four human HNSCC cell lines confirmed that these eight genes are indeed characteristic markers of CAFs. Immune cell infiltration differences analysis between high-risk and low-risk groups according to the eight CAF-related genes signature hinted at CAFs regulatory roles in the TIME, further revealing its potential role on prognosis. The signature of the eight CAF-related genes was validated in different independent validation cohorts and all showed that it was a valid marker for prognosis. The significantly higher overall survival (OS) in the low-risk group compared to the high-risk group was confirmed by Kaplan-Meier (K-M) analysis, suggesting that the signature of CAF-related genes can be used as a non-invasive predictive tool for HNSCC prognosis. The low-risk group had significantly higher levels of tumor-killing immune cell infiltration, as confirmed by CIBERSORT analysis, such as CD8+ T cells, follicular helper T cells, and Dendritic cells (DCs) in the low-risk group. In contrast, the level of infiltration of pro-tumor cells such as M0 macrophages and activated Mast cells (MCs) was lower. It is crucial to delve into the complex mechanisms between CAFs and immune cells to find potential regulatory targets and may provide new evidence for subsequently targeted immunotherapy. These results suggest that the signature of the eight CAF-related genes is a powerful indicator for the assessment of the TIME of HNSCC. It may provide a new and reliable potential indicator for clinicians to predict the prognosis of HNSCC, which may be used to guide treatment and clinical decision-making in HNSCC patients. Meanwhile, CAF-related genes are expected to become tumor biomarkers and effective targets for HNSCC.

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Background & Aims: The albumin-bilirubin (ALBI) score is calculated using serum levels of total bilirubin and albumin as a simple method to assess liver function. This study investigated the ability of baseline ALBI score/grade measurements to assess histological stage and disease progression in individuals with primary biliary cholangitis (PBC) in a large Japanese nationwide cohort. Methods: A total of 8,768 Japanese patients with PBC were enrolled between 1980 and 2016 from 469 institutions, among whom 83% received ursodeoxycholic acid (UDCA) only, 9% received UDCA and bezafibrate, and 8% were given neither drug. Baseline clinical and laboratory parameters were retrospectively retrieved and reviewed from a central database. Associations of ALBI score/grade with histological stage, mortality, and need for liver transplantation (LT) were evaluated using Cox proportional hazards models. Results: During the median follow-up period of 5.3 years, 1,227 patients died (including 789 from liver-related causes) and 113 underwent LT. ALBI score and ALBI grade were significantly associated with Scheuer's classification (both p <0.0001). ALBI grade 2 or 3 had significant associations with all-cause mortality or need for LT as well as liver-related mortality or need for LT according to Cox proportional hazards regression analysis (hazard ratio 3.453, 95% CI 2.942-4.052 and hazard ratio 4.242, 95% CI 3.421-5.260, respectively; both p <0.0001). Cumulative LT-free survival rates at 5 years in the ALBI grade 1, 2, and 3 groups were 97.2%, 82.4%, and 38.8%, respectively, while respective non-liver-related survival rates were 98.1%, 86.0%, and 42.0% (both p <0.0001, log-rank test). Conclusions: This large nationwide study of patients with PBC suggested that baseline measurements of ALBI grade were a simple non-invasive predictor of prognosis in PBC. Impact and implications: Primary biliary cholangitis (PBC) is an autoimmune liver disease characterized by progressive destruction of intrahepatic bile ducts. This study examined the ability of albumin-bilirubin (ALBI) score/grade to estimate histological findings and disease progression in PBC by means of a large-scale nationwide cohort in Japan. ALBI score/grade were significantly associated with Scheuer's classification stage. Baseline ALBI grade measurements may be a simple non-invasive predictor of prognosis in PBC.

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Purpose: To determine the cumulative incidence of strabismus surgery after pediatric cataract surgery and identify the associated risk factors. Design: US population-based insurance claims retrospective cohort study. Participants: Patients ≤ 18 years old who underwent cataract surgery in 2 large databases: Optum Clinformatics Data Mart (2003-2021) and IBM MarketScan (2007-2016). Methods: Individuals with at least 6 months of prior enrollment were included, and those with a history of strabismus surgery were excluded. The primary outcome was strabismus surgery within 5 years of cataract surgery. The risk factors investigated included age, sex, persistent fetal vasculature (PFV), intraocular lens (IOL) placement, nystagmus and strabismus diagnoses before cataract surgery, and cataract surgery laterality. Main Outcome Measures: Kaplan-Meier estimated cumulative incidence of strabismus surgery 5 years after cataract surgery and hazard ratios (HRs) with 95% confidence intervals (CIs) from multivariable Cox proportional hazards regression models. Results: Strabismus surgery was performed on 271/5822 children included in this study. The cumulative incidence of strabismus surgery within 5 years after cataract surgery was 9.6% (95% CI, 8.3%-10.9%). Children who underwent strabismus surgery were more likely to be of younger age at the time of cataract surgery, of female sex, have a history of PFV or nystagmus, have a pre-existing strabismus diagnosis, and less likely to have an IOL placed (all P < 0.001). Factors associated with strabismus surgery in the multivariable analysis included age 1 to 4 years (HR, 0.50; 95% CI, 0.36-0.69; P < 0.001) and age > 5 years (HR, 0.13; 95% CI, 0.09-0.18; P < 0.001) compared with age < 1 year at time of cataract surgery, male sex (HR, 0.75; 95% CI, 0.59-0.95; P < 0.001), IOL placement (HR, 0.71; 95% CI, 0.54-0.94; P = 0.016), and strabismus diagnosis before cataract surgery (HR, 4.13; 95% CI, 3.17-5.38; P < 0.001). Among patients with strabismus diagnosis before cataract surgery, younger age at cataract surgery was the only factor associated with increased risk of strabismus surgery. Conclusions: Approximately 10% of patients will undergo strabismus surgery within 5 years after pediatric cataract surgery. Children of younger age, female sex, and with a pre-existing strabismus diagnosis undergoing cataract surgery without IOL placement are at greater risk. Financial Disclosures: The author(s) have no proprietary or commercial interest in any materials discussed in this article.

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Background & Aims: We elucidated the clinical and immunologic implications of serum IL-6 levels in patients with unresectable hepatocellular carcinoma (HCC) treated with atezolizumab and bevacizumab (Ate/Bev). Methods: We prospectively enrolled 165 patients with unresectable HCC (discovery cohort: 84 patients from three centres; validation cohort: 81 patients from one centre). Baseline blood samples were analysed using a flow cytometric bead array. The tumour immune microenvironment was analysed using RNA sequencing. Results: In the discovery cohort, clinical benefit 6 months (CB6m) was defined as complete or partial response, or stable disease for ≥6 months. Among various blood-based biomarkers, serum IL-6 levels were significantly higher in participants without CB6m than in those with CB6m (mean 11.56 vs. 5.05 pg/ml, p = 0.02). Using maximally selected rank statistics, the optimal cut-off value for high IL-6 was determined as 18.49 pg/ml, and 15.2% of participants were found to have high IL-6 levels at baseline. In both the discovery and validation cohorts, participants with high baseline IL-6 levels had a reduced response rate and worse progression-free and overall survival after Ate/Bev treatment compared with those with low baseline IL-6 levels. In multivariable Cox regression analysis, the clinical implications of high IL-6 levels persisted, even after adjusting for various confounding factors. Participants with high IL-6 levels showed reduced interferon-γ and tumour necrosis factor-α secretion from CD8+ T cells. Moreover, excess IL-6 suppressed cytokine production and proliferation of CD8+ T cells. Finally, participants with high IL-6 levels exhibited a non-T-cell-inflamed immunosuppressive tumour microenvironment. Conclusions: High baseline IL-6 levels can be associated with poor clinical outcomes and impaired T-cell function in patients with unresectable HCC after Ate/Bev treatment. Impact and implications: Although patients with hepatocellular carcinoma who respond to treatment with atezolizumab and bevacizumab exhibit favourable clinical outcomes, a fraction of these still experience primary resistance. We found that high baseline serum levels of IL-6 correlate with poor clinical outcomes and impaired T-cell response in patients with hepatocellular carcinoma treated with atezolizumab and bevacizumab.

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Background: Herpes zoster (HZ) and associated complications cause significant burden to older people. A HZ vaccination programme was introduced in Aotearoa New Zealand in April 2018 with a single dose vaccine for those aged 65 years and a four-year catch up for 66-80 year-olds. This study aimed to assess the 'real-world' effectiveness of the zoster vaccine live (ZVL) against HZ and postherpetic neuralgia (PHN). Methods: We conducted a nationwide retrospective matched cohort study from 1 April 2018 to 1 April 2021 using a linked de-identified patient level Ministry of Health data platform. A Cox proportional hazards model was used to estimate ZVL vaccine effectiveness (VE) against HZ and PHN adjusting for covariates. Multiple outcomes were assessed in the primary (hospitalised HZ and PHN - primary diagnosis) and secondary (hospitalised HZ and PHN: primary and secondary diagnosis, community HZ) analyses. A sub-group analysis was carried out in, adults ≥ 65 years old, immunocompromised adults, Maori, and Pacific populations. Findings: A total of 824,142 (274,272 vaccinated with ZVL matched with 549,870 unvaccinated) New Zealand residents were included in the study. The matched population was 93.4% immunocompetent, 52.2% female, 80.2% European (level 1 ethnic codes), and 64.5% were 65-74 years old (mean age = 71.1±5.0). Vaccinated versus unvaccinated incidence of hospitalised HZ was 0.16 vs. 0.31/1,000 person-years and 0.03 vs. 0.08/1000 person-years for PHN. In the primary analysis, the adjusted overall VE against hospitalised HZ and hospitalised PHN was 57.8% (95% CI: 41.1-69.8) and 73.7% (95% CI:14.0-92.0) respectively. In adults ≥ 65 years old, the VE against hospitalised HZ was 54.4% (95% CI: 36.0-67.5) and VE against hospitalised PHN was 75·5% (95% CI: 19.9-92.5). In the secondary analysis, the VE against community HZ was 30.0% (95% CI: 25.6-34.5). The ZVL VE against hospitalised HZ for immunocompromised adults was 51.1% (95% CI: 23.1-69.5), and PHN hospitalisation was 67.6% (95% CI: 9.3-88.4). The VE against HZ hospitalisation for Maori was 45.2% (95% CI: -23.2-75.6) and for Pacific Peoples was 52.2% (95% CI: -40.6 -83·7). Interpretation: ZVL was associated with a reduction in risk of hospitalisation from HZ and PHN in the New Zealand population. Funding: Wellington Doctoral Scholarship awarded to JFM.

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Head and neck radiotherapy induces important toxicity, and its efficacy and tolerance vary widely across patients. Advancements in radiotherapy delivery techniques, along with the increased quality and frequency of image guidance, offer a unique opportunity to individualize radiotherapy based on imaging biomarkers, with the aim of improving radiation efficacy while reducing its toxicity. Various artificial intelligence models integrating clinical data and radiomics have shown encouraging results for toxicity and cancer control outcomes prediction in head and neck cancer radiotherapy. Clinical implementation of these models could lead to individualized risk-based therapeutic decision making, but the reliability of the current studies is limited. Understanding, validating and expanding these models to larger multi-institutional data sets and testing them in the context of clinical trials is needed to ensure safe clinical implementation. This review summarizes the current state of the art of machine learning models for prediction of head and neck cancer radiotherapy outcomes.

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Background: Evidence of factors associated with Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) from population-based studies is scarce. Objective: We aimed to identify the incidence, risk factors, and drugs that trigger the development of SJS/TEN in the general population. Methods: A regional, population-based, longitudinal cohort with 2,398,393 Japanese individuals was analyzed using the Shizuoka Kokuho Database from 2012 to 2020. Results: Among 1,909,570 individuals, 223 (0.01%, 2.3 cases/100,000 person-years) patients were diagnosed with SJS/TEN during the observational period of a maximum of 7.5 years. In a multivariable analysis, the risks of SJS/TEN were an older age, and the presence of type 2 diabetes, peripheral vascular disease, and systemic autoimmune diseases. The administration of drugs, such as immune checkpoint inhibitors, insulin, and type 2 diabetes agents, triggered the onset of SJS/TEN. Limitations: The results may apply only to the Japanese population. Conclusion: In this cohort population from a database representing the general population, the risks of developing SJS/TEN were old age and a history of type 2 diabetes, peripheral vascular disease, and systemic autoimmune disease. Furthermore, in addition to previously reported drugs, the administration of immune checkpoint inhibitors, insulin, and type 2 diabetes agents, may trigger the development of SJS/TEN.

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Background & Aims: Adverse muscle composition (MC) (i.e., low muscle volume and high muscle fat) has previously been linked to poor functional performance and comorbidities in non-alcoholic fatty liver disease (NAFLD). In this study we aimed to investigate associations of all-cause mortality with liver fat, NAFLD, and MC in the UK Biobank imaging study. Methods: Magnetic resonance images of 40,174 participants were analyzed for liver proton density fat fraction (PDFF), thigh fat-free muscle volume (FFMV) z-score, and muscle fat infiltration (MFI) using the AMRA® Researcher. Participants with NAFLD were sex-, age-, and BMI-matched to participants without NAFLD with low alcohol consumption. Adverse MC was identified using previously published cut-offs. All-cause mortality was investigated using Cox regression. Models within NAFLD were crude and subsequently adjusted for sex, age, BMI (M1), hand grip strength, physical activity, smoking, alcohol (M2), and previous cancer, coronary heart disease, type 2 diabetes (M3). Results: A total of 5,069 participants had NAFLD. During a mean (±SD) follow-up of 3.9 (±1.4) years, 150 out of the 10,138 participants (53% men, age 64.4 [±7.6] years, BMI 29.7 [±4.4] kg/m2) died. In the matched dataset, neither NAFLD nor liver PDFF were associated with all-cause mortality, while all MC variables achieved significance. Within NAFLD, adverse MC, MFI and FFMV z-score were significantly associated with all-cause mortality and remained so in M1 and M2 (crude hazard ratios [HRs] 2.84, 95% CI 1.70-4.75, p <0.001; 1.15, 95% CI 1.07-1.24, p <0.001; 0.70, 95% CI 0.55-0.88, p <0.001). In M3, the relationship was attenuated for adverse MC and FFMV z-score (adjusted HRs 1.72, 95% CI 1.00-2.98, p = 0.051; 0.77, 95% CI 0.58-1.02, p = 0.069) but remained significant for MFI (adjusted HR 1.13, 95% CI 1.01-1.26, p = 0.026). Conclusions: Neither NAFLD nor liver PDFF was predictive of all-cause mortality. Adverse MC was a strong predictor of all-cause mortality in individuals with NAFLD. Impact and implications: Individuals with fatty liver disease and poor muscle health more often suffer from poor functional performance and comorbidities. This study shows that they are also at a higher risk of dying. The study results indicate that measuring muscle health (the patient's muscle volume and how much fat they have in their muscles) could help in the early detection of high-risk patients and enable targeted preventative care.

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Background: Brain metastases (BM) occur in the natural course of malignant tumors in 18-40% of cases. Their management has changed considerably over the past decade thanks to the advent of Gamma knife Stereotactic Radiosurgery (GKSR). Objective: We report our experience on Single Brain metastasis treated with (GKSR). Methods: Patients treated by Gamma Knife stereotaxic radiosurgery (GKSR) in our institution between 2009 and 2021 for Single BM were recorded retrospectively. Results: A total of 103 patients (n = 52; 50.5% females) were included, with a mean age of 56.33 ± 11.33. Breast (n = 39, 37.9%) and lung (n = 36, 35%) were the common original location for the primary tumors. GKSR alone without prior surgery, radiotherapy, or chemotherapy was achieved in 81.5% (n = 84). Thirteen patients (15.1%) progressed in BM volume while finding the appearance of de novo BM in 5 (5.8%) patients. The median percentage of tumor control after radiosurgery treatment was 70% (IQR: 65-78) and only 26.2% (n = 27) of patients had > 80% tumor control and stability over the median follow-up time of 5 (95% CI, 4-6) months. We found only two cases of radionecrosis (1.9%). The median survival time was 5.21 (IQR, 3-8) months. Retreatment, recursive partitioning analysis (RPA) class, and tumor stability influenced the overall survival of BM respectively (Hazard Ratio adjust (HRa)= 5.610,p = 0.045; HRa= 6.133,p = 0.031; HRa= 22.463, p = 0.036). Conclusion: Stereotaxic Radiosurgery provides good results in terms of Overall survival with fewer neurocognitive disorders.RPA class and tumor control (stability) influenced the overall survival of single BM.

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With the increasing threat of metabolic syndromes, a focus on maintaining kidney health from early- to mid-adulthood is necessary. This study elucidates mortality risk and years of life lost (YLLs) due to abnormal renal function. This was a retrospective, matched cohort study from health checkup data from 2000 to 2015. We identified 12,774 participants with abnormal renal function (eGFR < 60 mL/min/1.73 m2) and used propensity score matching to identify 25,548 participants with normal renal function (eGFR ≥ 60). YLLs were estimated using the life expectancy differences between the abnormal and matched normal cohorts. Cox models were used to estimate the adjusted mortality risk. The estimated life expectancy of participants with proteinuria and eGFR < 60 was 26.24 years, with a 95 % confidence interval of (23.96, 29.36), 17.62 (16.37, 18.78), and 11.70 (11.02, 12.46) for age groups of 30 - 54, 55 - 64, and 65 - 79 years, respectively. The estimated YLLs of participants with proteinuria and eGFR < 60, as compared with the matched normal cohort, were 17.86 (13.41, 20.36), 12.55 (11.41, 13.78), and 8.31 (7.47, 9.13) years for the three age groups, respectively. The Cox model estimates of mortality hazard ratios of participants having proteinuria and eGFR < 60 against matched referents were 5.29 (3.97, 7.05), 3.99 (3.34, 4.75), and 3.05 (2.62, 3.55) for the three age groups, respectively. Abnormal renal function shortens life expectancy, particularly in patients with proteinuria and in younger adults. Active health management of renal function can reduce the disease burden.

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Objective: The standard of care in patients with solitary brain metastasis involves surgical resection and postoperative whole-brain radiotherapy (WBRT). However, WBRT is associated with adverse effects, mainly neurocognitive deterioration. Stereotactic radiosurgery (SRS) is a more targeted form of radiation therapy that could be as effective as WBRT without the detrimental neurocognitive decline. Methods: We performed the first systematic review and meta-analysis comparing postoperative SRS versus postoperative WBRT in patients with one resected brain metastasis. PubMed, Scopus, and Cochrane library were systematically searched for studies comparing the efficacy of the two radiation modalities in terms of local and distant brain control, leptomeningeal disease control, and overall survival. Additionally, we extracted patients' neurocognitive function and quality of life after each postoperative radiation form. Results: Four studies with 248 patients (128: WBRT, 120: SRS) were included in our analysis. There was no difference between SRS and WBRT in the risk of local recurrence (RR = 0.92, CI = 0.51-1.66, p = 0.78, I2 = 0%) and leptomeningeal disease (RR = 1.21, CI = 0.49-2.98, p = 0.67, I2 = 18%), neither in the patients' overall survival (HR = 1.06, CI = 0.61-1.85, p = 0.83, I2 = 63%). Nevertheless, SRS appeared to increase the risk of distant brain failure (RR = 2.03, CI = 0.94-4.40, p = 0.07, I2 = 61%). Neurocognitive function and quality of life in the SRS group were equal or superior to the WBRT group. Conclusions: Although SRS may increase the risk of distant brain failure, it appears to be as effective as WBRT in terms of local control, risk of leptomeningeal disease, and overall survival while sparing the patients of the detrimental, WBRT-associated cognitive deterioration.

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Background: At present, many studies have confirmed that inflammation plays a central role in Parkinson's disease (PD). The inflammatory index is related to the prognosis of the disease, but a single inflammatory index has some limitations. The C-reactive protein-albumin ratio (CAR) is a better marker of inflammation or nutritional status than C-reactive protein (CRP) or albumin (Alb), but there is limited study on the association between CAR and the overall survival (OS) of PD. Object: To study the association between CAR and OS in PD patients. Methods: All of these data were obtained from the Dryad Digital Repository, based on which we conducted a secondary analysis. The study was conducted by the Department of Neurology, the National Regional Center for Neurological Disorders, and the National Hospital of Utano study between March 2004 to November 2007. The final analytic sample included 235 PD patients with the outcome of survival or all-cause death from the study registration to the endpoint. In this study, univariate and multivariate COX regression analyses were used to calculate the adjusted hazard ratio (HR), with a 95% confidence interval (CI). In addition, the association between CAR and OS in PD patients was explored by Kaplan-Meier curve and subgroup analysis. Results: This study included 235 PD patients with an average age of 62.25 years, including 135 females and 100 males, and 45 died during the follow-up period. CAR was associated with gender, modified Hoehn-Yahr stages (mH-Y), and Mini-Mental State Examination (MMSE) of PD patients. In the COX multivariate regression model, after adjusting the age, gender, PD duration, mH-Y, MMSE, and the non-steroidal anti-inflammatory drugs, CAR was found to be associated with the OS in PD (HR = 1.54, 95% CI = 1.01-2.34, p = 0.044). Subgroup analysis showed that the subgroup did not play an interactive role in the association between the prognosis of patients with CAR and PD (p for interaction >0.05), and the results remained stable. Conclusions: The all-cause mortality of PD patients with a high level of CAR is higher, which indicates that the poor overall survival of PD patients is associated with the increase of CAR. The CAR may be a reliable prognostic biomarker for PD patients.

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Hepatitis B virus (HBV) infection is still one kind of the infectious diseases that seriously threaten human health. Nonalcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease worldwide. HBV infection complicated with NAFLD is increasingly common. This review mainly describes the interaction between HBV infection and NAFLD, the interaction between steatosis and antiviral drugs, and the prognosis of HBV infection complicated with NAFLD. Most studies suggest that HBV infection may reduce the incidence of NAFLD. NAFLD can promote the spontaneous clearance of hepatitis B surface antigen (HBsAg), but whether it affects antiviral efficacy has been reported inconsistently. HBV infection combined with NAFLD can promote the progression of liver fibrosis, especially in patients with severe steatosis. The outcome of HBV infection combined with NAFLD predisposing to the progression of HCC remains controversial.