A Prospective Randomized Trial of Neoadjuvant Chemohormonal Therapy vs Hormonal Therapy in Locally Advanced Prostate Cancer Treated by Radical Prostatectomy.

PURPOSE: Benefits of docetaxel-based neoadjuvant chemohormonal therapy (NCHT) before radical prostatectomy (RP) remain largely unknown. We explored whether docetaxel-based NCHT would bring pathological benefits and improve biochemical progression-free survival (bPFS) over neoadjuvant hormonal therapy (NHT) in locally advanced prostate cancer. MATERIALS AND METHODS: A randomized trial was designed recruiting 141 locally advanced, high-risk prostate cancer patients who were randomly assigned at the ratio of 2:1 to the NCHT group (75 mg/m2 body surface area every 3 weeks plus androgen deprivation therapy for 6 cycles) and the NHT group (androgen deprivation therapy for 24 weeks). The primary end point was 3-year bPFS. Secondary end points were pathological response including pathological downstaging and minimal residual disease rates. RESULTS: The NCHT group showed significant benefits in 3-year bPFS compared to the NHT group (29% vs 9.5%, P = .002). At a median follow-up of 53 months, the NCHT group achieved a significantly longer median bPFS time than the NHT group (17 months vs 14 months). No significant differences were found between the 2 groups in pathological downstaging and minimal residual disease rates. CONCLUSIONS: NCHT plus RP achieved significant bPFS benefits when compared with NHT plus RP in high-risk, locally advanced prostate cancer. A larger cohort with longer follow-up duration is essential in further investigation.

Assessing dynamic metabolic heterogeneity in prostate cancer patients via total-body [68Ga]Ga-PSMA-11 PET/CT imaging: quantitative analysis of [68Ga]Ga-PSMA-11 uptake in pathological lesions and normal organs.

PURPOSE: This study aimed to quantitatively assess [68Ga]Ga-PSMA-11 uptake in pathological lesions and normal organs in prostate cancer using the total-body [68Ga]Ga-PSMA-11 PET/CT and to characterize the dynamic metabolic heterogeneity of prostate cancer. METHODS: Dynamic total-body [68Ga]Ga-PSMA-11 PET/CT scans were performed on ten prostate cancer patients. Manual delineation of volume-of-interests (VOIs) was performed on multiple normal organs displaying high [68Ga]Ga-PSMA-11 uptake, as well as pathological lesions. Time-to-activity curves (TACs) were generated, and the four compartment models including one-tissue compartmental model (1T1k), reversible one-tissue compartmental model (1T2k), irreversible two-tissue compartment model (2T3k) and reversible two-tissue compartmental model (2T4k) were fitted to each tissue TAC. Various rate constants, including K1 (forward transport rate from plasma to the reversible compartment), k2 (reverse transport rate from the reversible compartment to plasma), k3 (tracer binding on the PSMA-receptor and its internalization), k4 (the externalization rate of the tracer) and Ki (net influx rate), were obtained. The selection of the optimal model for describing the uptake of both lesions and normal organs was determined using the Akaike information criteria (AIC). Receiver operating characteristic (ROC) curve analysis was performed to determine the cut-off values for differentiating physiological and pathological [68Ga]Ga-PSMA-11 uptake. RESULTS: Both 1T1k and 1T2k models showed relatively high AIC values compared to the 2T3k and 2T4k models in both pathological lesions and normal organs. The kinetic behavior of pathological lesions was better described by the 2T3k model compared to the 2T4k model, while the normal organs were better described by the 2T4k model. Significant variations in kinetic metrics, such as K1, k2, and k3, and Ki, were observed among normal organs with high [68Ga]Ga-PSMA-11 uptake and pathological lesions. The high Ki value in normal organs was primarily determined by elevated K1 and low k3, rather than k2. Conversely, the high Ki value in pathological lesions, ranking second to the kidney and similar to salivary glands and spleen, was predominantly determined by the highest k3 value. Notably, k3 exhibited the highest performance in distinguishing between physiological and pathological [68Ga]Ga-PSMA-11 uptake, with an area under the curve (AUC) of 0.844 (95% CI, 0.773-0.915), sensitivity of 82.9%, and specificity of 74.1%. The k3 values showed better performance than SUVmean (AUC, 0.659), SUVmax (AUC, 0.637), and other kinetic parameter including K1 (AUC, 0.604), k2 (AUC, 0.634), and Ki (AUC, 0.651). CONCLUSIONS: Significant discrepancies in kinetic metrics were detected between pathological lesions and normal organs, despite their shared high uptake of [68Ga]Ga-PSMA-11. Notably, the k3 value exhibits a noteworthy capability to distinguish between pathological lesions and normal organs with elevated [68Ga]Ga-PSMA-11 uptake. This discovery implies that k3 holds promise as a prospective imaging biomarker for distinguishing between pathologic and non-specific [68Ga]Ga-PSMA-11 uptake in patients with prostate cancer.

Comparison of parametric imaging and SUV imaging with [68 Ga]Ga-PSMA-11 using dynamic total-body PET/CT in prostate cancer.

PURPOSE: Standardized uptake value (SUV) has been prevalently used to measure [68 Ga]Ga-PSMA-11 activity in prostate cancer, but it is susceptible to multiple factors. Parametric imaging allows for absolute quantification of tracer uptake and provides a better diagnostic accuracy that is crucial for lesion detection. However, the clinical significance of total-body parametric imaging of [68 Ga]Ga-PSMA-11 remains to be fully assessed. Therefore, the aim of our study is to delve into the diagnostic implications of total-body parametric imaging of [68 Ga]Ga-PSMA-11 PET/CT for patients with prostate cancer. METHODS: Twenty prostate cancer patients were included and underwent a dynamic total-body [68 Ga]Ga-PSMA-11 PET/CT scan. An irreversible two-tissue compartment model (2T3k) was fitted for each tissue time-to-activity curve, and the net influx rate (Ki) was obtained. The image quality and semi-quantitative analysis of lesion-to-background ratio (LBR), signal-to-noise ratio (SNR), and contrast-to-noise ratio (CNR) were compared between parametric images and SUV images. RESULTS: Kinetic modeling using 2T3k demonstrated favorable model fitting in both normal organs and lesions. All of the lesions detected on SUV images (55-60 min) could be detected on Ki images. The correlation between Ki, SUVmean, and SUVmax in both normal organs and pathological lesions was found to be positive and statistically significant. Conversely, a moderate positive correlations were found between Ki and K1 (R = 0.69, P < 0.001; R = 0.61, P < 0.001) and Ki and k3 (R = 0.69, P < 0.001; R = 0.62, P < 0.001), in normal organs and pathological lesions, respectively. Visual assessment in Ki images showed less image noise and higher lesions conspicuity compared to SUV images. Ki image-derived LBR, SNR, and CBR of pathological lesions including primary tumors (PTs), lymph node metastases (LNMs) and bone metastases (BMs), exhibited remarkably higher folds (1.4-3.6 folds) compared to those derived from SUV of corresponding lesions. CONCLUSIONS: Total-body parametric imaging of [68 Ga]Ga-PSMA-11 enhanced lesion contrast and improved lesion detectability compared to SUV images. This may potentially serve as an imaging biomarker and theranostic tool for precise diagnosis and treatment evaluation in prostate cancer patients.

Types of fish consumption differ across socioeconomic strata and impact differently on plasma fish-based omega-3 fatty acids: a cross-sectional study.

PURPOSE: We investigated the associations of socioeconomic position (SEP) with total and type of fish intake in a large general population and validated whether types of fish intake were differently associated with plasma EPA and DHA in a subset of the population. METHODS: From the Lifelines Cohort Study, 94,246 participants aged 44 ± 13 years old were included to test the association of two SEP indicators, i.e., education level and household income level, with dietary intakes of total, oily, lean, fried, and other types of fish. In a subset of 575 participants (mean age: 50 ± 13 years), EPA and DHA levels were measured in plasma phospholipids and triglycerides. Dietary fish intake was assessed using Food Frequency Questionnaire. Linear regressions were applied and adjusted for relevant covariates. RESULTS: Compared to the high education level, lower education levels were negatively associated with total, oily, lean, and other fish intake (p < 0.001 for all), and positively associated with fried fish intake (ß (SE): 0.04 (0.04), p < 0.001 for middle education; 0.07 (0.04), p < 0.001 for low education), independently of relevant covariates. Similar results were observed for income levels. In the subset population, total and oily fish intakes were positively associated with plasma EPA and DHA (p < 0.02 for all). Lean and other fish intakes were positively associated with only DHA (p < 0.008 for all), but not EPA, while fried fish was not associated with either EPA or DHA in plasma (p > 0.1 for all). CONCLUSION: Lower SEP was associated with a lower total intake of fish, and of oily and lean fish, but with higher intake of fried fish. Fried fish was not associated with the fish-based EPA and DHA in plasma. Hence, SEP-related differences in fish consumption are both quantitative and qualitative.

New insights into the paradox between smoking and the risk of SARS-CoV-2 infection (COVID-19): Insufficient evidence for a causal association.

AIMS: Previous studies have reported a 'smoker's paradox', where people who smoke appear to be protected against Severe Acute Respiratory Syndrome CoronaVirus-2 (SARS-CoV-2) infection (COVID-19). This conflicts with well-established evidence that people who smoke are generally more vulnerable to respiratory infections. In this study, we aimed to validate the association between smoking and SARS-CoV-2 infection in a general Dutch population, and to evaluate the evidence underlying the possible causal relationship between smoking and SARS-CoV-2 infection by applying a modern adaptation of the Bradford Hill criteria. METHODS: In total, 57,833 participants from the Lifelines Cohort Study were included in the analysis. Smoking status, including never smoker, current smoker, and former smoker, was derived from the Lifelines general assessment between 2014 and 2017, while SARS-CoV-2 infection status was derived from an additional COVID-19 questionnaire from 2021 to 2022. Logistic regressions were used for the association between smoking status and infection status. The adapted Bradford Hill's criteria, including the strength of association (including an analysis of plausible confounding), plausibility, temporality and study design suitability, were applied to evaluate the existing literature. RESULTS: We found, compared with never smokers, an increased risk of SARS-CoV-2 infection for former smokers (odds ratio (OR)=1.07, 95% confidence interval (CI)=1.01-1.13), but a reduced risk for current smokers (OR=0.85, 95% CI=0.79-0.92), after adjusting for several relevant covariates. However, we discerned a possible explanation of the smoker's paradox since we observed that current smokers were more likely to be non-responders to the COVID-19 questions and, more importantly, these non-responders were more likely to have other established risk factors for SARS-CoV-2 infection. CONCLUSIONS: There is insufficient evidence to suggest that smoking protects against SARS-CoV-2 infection. According to the adapted Bradford Hill's criteria, we observed a high inconsistency between study results, a high possibility for residual confounding and no clear evidence for biological plausibility. Future studies should include linkage with the confirmed testing results from national healthcare registries to mitigate avoidable bias.

Differently Distributed Iron Deposition in Mild and Moderate Stroke with Small Artery Occlusion: A Pilot Voxel-Based Susceptibility Mapping Study.

BACKGROUND: Small artery occlusion (SAO) is a common ischemic stroke subtype. However, its clinical outcome can be more severe than commonly understood. The severity of SAO can vary, ranging from mild to moderate. Iron deposition has been associated with the development and progression of stroke. However, its specific distribution and relationship with stroke severity in SAO remain unclear. The study's purpose is to investigate the differences in iron deposition between mild stroke with SAO (SAO-MiS) and moderate stroke with SAO (SAO-MoS) through quantitative susceptibility mapping (QSM) and its association with neurological deficits. METHODS: Sixty-eight SAO participants within 24 hours of first onset were enrolled and separated into SAO-MiS and SAO-MoS according to the National Institutes of Health Stroke Scale (NIHSS) scores. QSM helped calculate the susceptibility maps, reflecting the iron content within the brain. The susceptibility maps were analyzed using voxel-wise statistical analysis to compare the iron deposition between SAO-MiS and SAO-MoS. Then, differentially distributed iron deposition helped differentiate between mild and moderate stroke using support vector machine (SVM) methods. RESULTS: Compared with SAO-MiS, SAO-MoS depicted elevated iron deposition in the left pallidum, parahippocampal gyrus, and superior frontal gyrus medial region, and is lower in the right superior/middle frontal gyrus and bilateral supplementary motor area. Based on iron deposition, the SVM classifier's analysis revealed a high power to discriminate SAO-MoS from SAO-MiS. In addition, fibrinogen, triglyceride (TG), and total cholesterol (TC) were linked with QSM values in specific brain regions. CONCLUSIONS: Our study first revealed the brain iron distribution after SAO and differently distributed iron deposition in SAO-MiS and SAO-MoS. The results indicate that iron deposition could play a role in the pathophysiology of SAO and its correlation with stroke severity.

Baseline PSMA-PET/CT as a predictor of PSA persistence following radical prostatectomy in high-risk nonmetastatic prostate cancer patients receiving neoadjuvant therapy.

BACKGROUND: The precise staging and proper management of high-risk prostate cancer (PCa) continues to be a challenge. We aimed to demonstrate the prognostic value of baseline prostate-specific membrane antigen-ligand positron emission tomography/computed tomography (PSMA-PET/CT) in high-risk, nonmetastatic PCa patients who received neoadjuvant hormonal or chemohormonal treatment followed by radical prostatectomy (RP). METHODS: We performed retrospective analyses of 70 patients with high-risk, nonmetastatic PCa confirmed by biopsy between 2018 and 2021. All patients underwent neoadjuvant therapy followed by RP and pelvic lymph node dissection (PLND); PSMA-PET/CT was performed before initiation of neoadjuvant therapy. Acquired image information and clinical characteristics/outcomes were examined for possible associations. RESULTS: Among 70 high-risk PCa patients, median age was 69 years old and median prostate specific antigen (PSA) at presentation was 58.5 ng/mL. Thirty (42.9%) patients had uptake of the PSMA tracer only in the primary PCa lesions and 40 (57.1%) patients had PSMA-positive lesions in regional or distant sites. Sixteen (32%) localized PCa patients defined by pre-PET magnetic resonance imaging were found to have locally advanced PCa based on PSMA-PET/CT. Fifteen (30%) localized PCa patients and 7 (35%) locally advanced PCa patients were upstaged to metastatic PCa. The sensitivity and specificity of PSMA-PET/CT for the detection of lymph node involvement were 90.9% and 69.5%, respectively, with a positive prediction value of 35.7% and negative prediction value of 97.6%. The diagnostic accuracy was 72.9%. Univariate analysis showed upstaging, tumor stage, and metastasis location based on PSMA-PET/CT are predictors to PSA persistence after surgery, while multivariate logistic regression analysis showed only the tumor stage based on PSMA-PET/CT remained an independent predictor of the outcome. CONCLUSIONS: This study further highlights the accuracy and necessity of PSMA-PET/CT in newly diagnosed, high-risk, nonmetastatic PCa patients.

Total-body [68 Ga]Ga-PSMA-11 PET/CT improves detection rate compared with conventional [68 Ga]Ga-PSMA-11 PET/CT in patients with biochemical recurrent prostate cancer.

PURPOSE: The purpose of this study was to assess whether total-body [68 Ga]Ga-PSMA-11 PET/CT could improve the detection rate compared with conventional [68 Ga]Ga-PSMA-11 PET/CT in patients with biochemical recurrent prostate cancer. METHODS: Two hundred biochemical recurrent prostate cancer patients with similar clinicopathological characteristics were included, of whom 100 patients underwent early total-body [68 Ga]Ga-PSMA-11 PET/CT and diuretic-delayed total-body [68 Ga]Ga-PSMA-11 PET/CT, and the other 100 patients received early conventional [68 Ga]Ga-PSMA-11 PET/CT and diuretic-delayed conventional [68 Ga]Ga-PSMA-11 PET/CT. The detection rates of total-body [68 Ga]Ga-PSMA-11 PET/CT and conventional [68 Ga]Ga-PSMA-11 PET/CT were compared using a chi-square test and stratified analysis. The image quality of total-body [68 Ga]Ga-PSMA PET/CT and conventional [68 Ga]Ga-PSMA-11 PET/CT was compared based on subjective scoring and objective parameters. Subjective scoring was conducted from background noise and lesion prominence using a 5-point scale. Objective parameters were evaluated by SUVmax, SUVmean, the standard deviation (SD) of SUV, and the signal-to-noise ratio (SNR) of liver and gluteus maximus. The SUVmax of the recurrent lesions was also measured. RESULTS: The liver SD of the total-body [68 Ga]Ga-PSMA-11 PET/CT was significantly lower than that of conventional [68 Ga]Ga-PSMA-11 PET/CT, the SNR was significantly higher than that of conventional [68 Ga]Ga-PSMA-11 PET/CT, and the subjective evaluation was significantly better than that of conventional [68 Ga]Ga-PSMA-11 PET/CT. The detection rate of total-body [68 Ga]Ga-PSMA PET/CT for biochemical recurrence of prostate cancer was significantly higher than that of conventional [68 Ga]Ga-PSMA-11 PET/CT (91.0% vs. 74.0%, P = 0.003). Total-body [68 Ga]Ga-PSMA-11 PET/CT had better detection efficiency for patients with a Gleason score ≤ 8 or PSA ≤ 2 ng/ml. The advantages of diuretic-delayed total-body [68 Ga]Ga-PSMA-11 PET/CT were more obvious. CONCLUSION: Total-body [68 Ga]Ga-PSMA-11 PET/CT could significantly improve the detection rate compared with conventional [68 Ga]Ga-PSMA-11 PET/CT in patients with biochemical recurrent prostate cancer.

The application of "S.I.S" technique improves long-term continence after robotic radical prostatectomy.

AIMS: To propose a novel S.I.S technique during the robotic-assisted radical prostatectomy (RARP), encompassing pubourethral suspension, posterior wall intensification, and bladder neck stripping, and to present functional and oncological outcomes with a special focus on long-term continence. METHODS: From January 1, 2018, to December 31, 2019, consecutive patients who underwent RARP were retrospectively investigated and separated into the S.I.S group and the conventional group. Preoperative patient characteristics, tumor status, and perioperative parameters were collected, followed by the assessment of self-reported status on continence, using an International Consultation on Incontinence Modular Questionnaire-urinary incontinence short form (ICIQ-UI-SF). Statistical comparisons were performed on variables between the two surgery groups, and multivariate logistic regression analysis was used to determine predictive factors for postoperative incontinence severity. RESULTS: A total of 602 subjects were analyzed with a median follow-up of 24 months. There was no significant difference regarding baseline characteristics and perioperative parameters, except for a more advanced tumor stage in the S.I.S group. The application of the S.I.S technique did not jeopardize the positive surgical margin rate at the bladder neck or long-term tumor control. Notably, the patient-reported degree of incontinence was significantly reduced with the assistance of S.I.S technique, as evidenced by the diminished severe-to-very severe cases. On multivariate analysis, both preoperative body mass index and use of S.I.S modification were independent predictive factors for the long-term incontinence severity. CONCLUSIONS: The application of S.I.S technique during RARP is feasible and superior compare with the conventional approach, with a significantly alleviated long-term incontinence severity, without compromising cancer control.

Socio-economic gradients in diagnosed and undiagnosed Type 2 diabetes and its related health complications.

BACKGROUND AND AIMS: Diagnosed and undiagnosed Type 2 Diabetes (T2D) remains a challenge in high-income countries. In addition, the presence of T2D can cause further disease burden because of its high susceptibility to complications. Nevertheless, there is limited evidence of socio-economic gradients in undiagnosed T2D and its complications in a large population cohort. We investigated this using the Dutch Lifelines Cohort Study (Lifelines). METHODS AND RESULTS: Within Lifelines, baseline data of 102 163 adults aged 30 and above were collected from 2007 to 2013. The associations of Socio-Economic Status (SES), indicated by monthly household income, with the prevalence of T2D status and the number of T2D complications were assessed using multinomial Poisson and linear regressions with adjustments for age and sex. The prevalence of diagnosed and undiagnosed T2D was, respectively, 3.0% and 3.0% in the low SES group compared to 1.1% and 1.8% in the high SES group. Individuals with lower SES were at higher risk of having undiagnosed T2D (relative risk ratio (rrr) [95% CI]: 1.63 [1.47-1.81] for low SES and 1.16 [1.05-1.29] for middle SES) and diagnosed T2D, compared with those with high SES. Lower SES was positively associated with the number of T2D complications (low SES vs. high SES (ref); B [95% CI]: 0.15 [0.13-0.16]). CONCLUSION: Complementing the known socio-economic gradients in diagnosed T2D, we document socio-economic gradients in undiagnosed T2D and T2D complications in a single, large general representative population. Furthermore, individuals with low SES with diagnosed or undiagnosed T2D were more susceptible to T2D complications.

Identification of characteristic metabolic panels for different stages of prostate cancer by 1H NMR-based metabolomics analysis.

BACKGROUND: Prostate cancer (PCa) is the second most prevalent cancer in males worldwide, yet detecting PCa and its metastases remains a major challenging task in clinical research setups. The present study aimed to characterize the metabolic changes underlying the PCa progression and investigate the efficacy of related metabolic panels for an accurate PCa assessment. METHODS: In the present study, 75 PCa subjects, 62 PCa patients with bone metastasis (PCaB), and 50 benign prostatic hyperplasia (BPH) patients were enrolled, and we performed a cross-sectional metabolomics analysis of serum samples collected from these subjects using a 1H nuclear magnetic resonance (NMR)-based metabolomics approach. RESULTS: Multivariate analysis revealed that BPH, PCa, and PCaB groups showed distinct metabolic divisions, while univariate statistics integrated with variable importance in the projection (VIP) scores identified a differential metabolite series, which included energy, amino acid, and ketone body metabolism. Herein, we identified a series of characteristic serum metabolic changes, including decreased trends of 3-HB and acetone as well as elevated trends of alanine in PCa patients compared with BPH subjects, while increased levels of 3-HB and acetone as well as decreased levels of alanine in PCaB patients compared with PCa. Additionally, our results also revealed the metabolic panels of discriminant metabolites coupled with the clinical parameters (age and body mass index) for discrimination between PCa and BPH, PCaB and BPH, PCaB and PCa achieved the AUC values of 0.828, 0.917, and 0.872, respectively. CONCLUSIONS: Overall, our study gave successful discrimination of BPH, PCa and PCaB, and we characterized the potential metabolic alterations involved in the PCa progression and its metastases, including 3-HB, acetone and alanine. The defined biomarker panels could be employed to aid in the diagnosis and classification of PCa in clinical practice.

Determination of optimal 68 Ga-PSMA PET/CT imaging time in prostate cancers by total-body dynamic PET/CT.

BACKGROUND: 68 Ga-PSMA PET/CT has been widely used in patients with prostate cancer. Due to the limited axial field of view of conventional PET scanners, whole-body dynamic 68 Ga-PSMA PET/CT has not been performed. We investigated the time-activity curves (TACs) of prostate cancer pathological lesions and physiologic bladder activity to determine the optimal 68 Ga-PSMA PET/CT imaging time by total-body (TB) PET/CT. METHODS: Dynamic TB-PET performed on 11 patients with prostate cancer was analyzed. TACs were obtained by drawing regions of interest in normal organs and pathological lesions (primary prostate lesions and lymph nodes and bone metastases). We evaluated the 68 Ga-PSMA uptake pattern of normal organs, urinary bladder, and pathological lesions. RESULTS: The urinary bladder TAC increased slowly between 180 and 330 s post-injection and then rapidly between 5.5 and 60.0 min post-injection. The pathological lesion uptake increased rapidly during the first 5 min post-injection and then slowly through the remaining 55 min. Six minutes post-injection was the optimal time with the highest pathological lesion SUVmean values still higher than the urinary bladder activity value. However, these prostate lesion, lymph node metastasis, and bone metastasis SUVmean values were one-third, one-half, and one-half the corresponding values 60 min post-injection, suggesting that early imaging might miss low PSMA uptake lesions. A minimum of 35 min post-injection was required for the pathological lesions to have SUVmean values similar to the corresponding values at 60 min post-injection (all P > 0.05), even though the pathological lesion SUVmean values showed a continuous upward trend through the 60 min. CONCLUSIONS: Combining early dynamic 68 Ga-PSMA PET (75-360 s) and conventional static imaging 60 min post-injection could avoid the urinary bladder activity interference to better detect pathological lesions and lesions with relatively low PSMA uptake. The pathological lesion SUVmean values at 35-59 min and 60 min post-injection were similar, so 68 Ga-PSMA PET imaging could also be made at 35-59 min post-injection.

Effects of Education and Income on Incident Type 2 Diabetes and Cardiovascular Diseases: a Dutch Prospective Study.

BACKGROUND: Education and income, as two primary socioeconomic indicators, are often used interchangeably in health research. However, there is a lack of clear distinction between these two indicators concerning their associations with health. OBJECTIVE: This study aimed to investigate the separate and combined effects of education and income in relation to incident type 2 diabetes and cardiovascular diseases in the general population. DESIGN AND PARTICIPANTS: Participants aged between 30 and 65 years from the prospective Dutch Lifelines cohort study were included. Two sub-cohorts were subsequently created, including 83,759 and 91,083 participants for a type 2 diabetes cohort and a cardiovascular diseases cohort, respectively. MAIN MEASURES: Education and income level were assessed by self-report questionnaires. The outcomes were incident type 2 diabetes and cardiovascular diseases (defined as the earliest non-fatal cardiovascular event). KEY RESULTS: A total of 1228 new cases of type 2 diabetes (incidence 1.5%) and 3286 (incidence 3.6%) new cases of cardiovascular diseases were identified, after a median follow-up of 43 and 44 months, respectively. Low education and low income (<1000 euro/month) were both positively associated with a higher risk of incident type 2 diabetes (OR 1.24 [95%CI 1.04-1.48] and OR 1.71 [95%CI 1.30-2.26], respectively); and with a higher risk of incident cardiovascular diseases (OR 1.15 [95%CI 1.04-1.28] and OR 1.24 [95%CI 1.02-1.52], respectively); independent of age, sex, lifestyle factors, BMI, clinical biomarkers, comorbid conditions at baseline, and each other. Results from the combined associations of education and income showed that within each education group, a higher income was associated with better health; and similarly, a higher education was associated with better health within each income group, except for the low-income group. CONCLUSIONS: Education and income were both independently associated with incident type 2 diabetes and cardiovascular diseases. The combined associations of these two socioeconomic indicators revealed that within each education or income level, substantial health disparities existed across strata of the other socioeconomic indicator. Education and income are two equally important socioeconomic indicators in health, and should be considered simultaneously in health research and policymaking.

Associations of 24 h urinary excretions of α- and γ-carboxyethyl hydroxychroman with plasma α- and γ-tocopherol and dietary vitamin E intake in older adults: the Lifelines-MINUTHE Study.

BACKGROUND: Urinary metabolites of vitamin E, i.e., α- and γ-carboxyethyl hydroxychroman (α- and γ-CEHC), have gained increasing attention and have been proposed as novel biomarkers of vitamin E intake and status. However, there are insufficient data on the relationship of plasma α-tocopherol and γ-tocopherol and dietary vitamin E intake with 24 h urinary excretions of α- and γ-CEHC. OBJECTIVES: We aimed to (1) investigate the associations of urinary α- and γ-CEHC/creatinine ratios and 24 h urinary excretions of α- and γ-CEHC with plasma α- and γ-tocopherol, respectively; (2) investigate the associations of urinary α- and γ-CEHC/creatinine ratios and 24 h urinary excretions of α- and γ-CEHC with dietary vitamin E intake, and we hypothesize that 24 h urinary excretions of α- and γ-CEHC will better correlate with vitamin E intake than urinary α- and γ-CEHC/creatinine ratios. DESIGN: 24 h Urine and plasma samples were collected from 1519 participants (60-75 years, male: 50%) included in the Lifelines-MINUTHE Study for the assessments of urinary α- and γ-CEHC/creatinine ratios and 24 h urinary excretions of α- and γ-CEHC, and plasma α- and γ-tocopherol. Among those participants, dietary vitamin E intake data from 387 participants were available from an externally validated Flower-Food Frequency Questionnaire (FFQ). The associations of plasma α- and γ-tocopherol, dietary vitamin E intake, with urinary α- and γ-CEHC were assessed using multivariate linear regressions. RESULTS: 24 h Urinary excretion of α-CEHC (median (IQR): 0.9 (0.3-2.4) µmol) was less than that of γ-CEHC (median (IQR): 1.5 (0.5-3.5) µmol). After adjustment for covariates, we found that 24 h urinary α-CEHC excretion and urinary α-CEHC/creatinine ratio were both positively associated with plasma α-tocopherol (std.beta: 0.06, p = 0.02; std.beta: 0.06, p = 0.01, respectively). Furthermore, the sum of 24 h urinary α- and γ-CEHC excretions was positively associated with dietary vitamin E intake (std.beta: 0.08; p = 0.03), whereas there was no relation between urinary α- and γ-CEHC/creatinine ratios and vitamin E intake. No association was observed neither between plasma α- and γ-tocopherol and dietary vitamin E intake, nor between urinary γ-CEHC and plasma γ-tocopherol. CONCLUSION: Our study confirmed our hypothesis that 24 h urinary α- and γ-CEHC excretions would be a better marker for dietary vitamin E intake than urinary α- and γ-CEHC/creatinine ratios. Considering that both 24 h urinary α- and γ-CEHC excretions and α- and γ-CEHC/creatinine ratios were also associated with plasma α-tocopherol status, we suggest that 24 h urinary α- and γ-CEHC excretions could be used to assess overall vitamin E status.

Frailty and risk of hospitalization from COVID-19 infection among older adults: evidence from the Dutch Lifelines COVID-19 Cohort study.

BACKGROUND: Frailty is associated with COVID-19 severity in clinical settings. No general population-based studies on the association between actual frailty status and COVID-19 hospitalization are available. AIMS: To investigate the association between frailty and the risk of COVID-19 hospitalization once infected. METHODS: 440 older adults who participated in the Lifelines COVID-19 Cohort study in the Northern Netherlands and reported positive COVID-19 testing results (54.2% women, age 70 ± 4 years in 2021) were included in the analyses. COVID-19 hospitalization status was self-reported. The Groningen Frailty Indicator (GFI) was derived from 15 self-reported questionnaire items related to daily activities, health problems, and psychosocial functioning, with a score ≥ 4 indicating frailty. Both frailty and COVID-19 hospitalization were assessed in the same period. Poisson regression models with robust standard errors were used to analyze the associations between frailty and COVID-19 hospitalization. RESULTS: Of 440 older adults included, 42 were hospitalized because of COVID-19 infection. After adjusting for sociodemographic and lifestyle factors, a higher risk of COVID-19 hospitalization was observed for frail individuals (risk ratio (RR) [95% CI] 1.97 [1.06-3.67]) compared to those classified as non-frail. DISCUSSION: Frailty was positively associated with COVID-19 hospitalization once infected, independent of sociodemographic and lifestyle factors. Future research on frailty and COVID-19 should consider biomarkers of aging and frailty to understand the pathophysiological mechanisms and manifestations between frailty and COVID-19 outcomes. CONCLUSIONS: Frailty was positively associated with the risk of hospitalization among older adults that were infected with COVID-19. Public health strategies for frailty prevention in older adults need to be advocated, as it is helpful to reduce the burden of the healthcare system, particularly during a pandemic like COVID-19.

HOXD13 suppresses prostate cancer metastasis and BMP4-induced epithelial-mesenchymal transition by inhibiting SMAD1.

The HOX genes are a group of highly conserved Homeobox-containing genes that control the body plan organization during development. However, their contributions to tumorigenesis and tumor progression remain uncertain and controversial. Here we provided evidence of tumor-suppressive activity of HOXD13 in prostate cancer. HOXD13 depletion contributes to more aggressiveness of prostate cancer cells in vitro and in vivo. These effects were corroborated in a metastatic mice model, where we observed more bone metastatic lesions formed by prostate cancer cells with HOXD13 ablation. Mechanistically, HOXD13 prevents BMP4-induced epithelial-mesenchymal transition (EMT) by inhibiting mothers against decapentaplegic homolog 1 (SMAD1) transcription. Both bioinformation and our tissue microarray cohort data show that HOXD13 expression inversely correlated in advanced prostate cancer patient specimens. Our findings establish HOXD13 as a negative regulator of prostate cancer progression and metastasis by preventing BMP4/SMAD1 signaling, and potentially suggest new strategies for targeting metastatic prostate cancer.

The prognostic nomogram including MRI for locally advanced prostate cancer treated by radical prostatectomy.

OBJECTIVE: To establish the prognostic nomogram for locally advanced prostate cancer (LAPC) patients treated by radical prostatectomy (RP) based on clinical and multiparametric-MRI (mp-MRI) metrics. METHODS: One hundred and twenty-one patients diagnosed with LAPC were included in this study. They were all examined by mp-MRI within one week before surgery and treated by RP (36 with RP alone, 48 with neoadjuvant hormonal therapy (NHT) and 37 with neoadjuvant chemohormonal therapy (NCHT)). The biochemical progression-free survival (bPFS) was analyzed by Kaplan-Meier method. Univariate and multivariate analysis were used to determine prognostic factors that were related with bPFS. The prognostic nomogram was established by factors that were significant in multivariate analyses. RESULTS: The median bPFS had significant difference in the subgroup of treatment (RP alone: 2 [0.00-5.04] vs. NHT: 9.3 [6.746-11.854] vs. NCHT: 11.17 [0.000-25.075] months [Log rank p < .001]), the subgroup of hyperintensity within prostate in DWI (negative: 15.97 [11.202-20.731] vs. positive: 5.2 [2.952-7.448] months [Log rank p < .001]) and the subgroup of pelvic lymph node metastasis (negative: 10.2 [8.404-11.996] vs. unilateral: 4.43 [0.000-11.086] vs. Bilateral: 1.83 [0.636~3.031] [Log rank p < .001]). The method of treatment (hazards ratio [HR], 0.566; 95% confidence interval [CI], 0.356-0.899; p = .016), hyperintensity within prostate in DWI (HR, 2.539; 95% CI, 1.349-4.779; p = .004) and the metastasis burden of pelvic lymph node (HR, 2.492; 95% CI, 1.645-3.777; p < .001) were identified as independent predictors with significance in multivariable Cox regression analysis. The nomogram was established based on these three factors. CONCLUSION: We established a nomogram based on three significant prognosis factors including the neoadjuvant therapeutic schedule, hyperintensity within prostate in DWI and the metastasis burden of pelvic lymph nodes, which were associated with the clinical outcomes in LAPC patients after surgery.

Targeted Next-Generation Sequencing Reveals Heterogenous Genomic Features in Viscerally Metastatic Prostate Cancer.

PURPOSE: We sought to explore the genomic features of bone-only metastasis, hepatic metastasis and pulmonary metastasis without liver involvement in prostate cancer using targeted next-generation sequencing. MATERIALS AND METHODS: A hybridization capture-based next-generation sequencing was performed to detected genomic alterations in 50 genes, including androgen receptor, DNA damage response and other clinical relevant drivers. RESULTS: We successfully sequenced circulating tumor DNA from 109 blood samples and 29 metastatic tissue samples from 129 patients with metastatic castration-resistant prostate cancer (metastatic castration-resistant prostate cancer). We observed distinct genomic profiles of metastatic castration-resistant prostate cancer across various metastatic sites. High prevalence of PTEN alteration was found in viscerally metastatic prostate cancer compared with bone-only metastatic prostate cancer (PTEN, 9.09% vs 2.08%, p=0.105). When comparing viscerally metastatic prostate cancer according to the metastatic sites, AR alteration rarely occurs in hepatically metastatic prostate cancer, which stood in great contrast to the high alteration frequency in hepatically metastatic prostate cancer (0.0% vs 42.1%, p=0.01). For overall DNA damage response alteration, the highest frequency was found in hepatically metastatic prostate cancer (63.2%). CONCLUSIONS: Through genomic profiling of prostate cancer across various metastatic sites, we identified an extremely low frequency of AR alterations in pulmonarily metastatic prostate cancer without liver involvement, high prevalence of DNA damage response pathway deficiency in hepatically metastatic prostate cancer and high PTEN alteration rates in viscerally metastatic prostate cancer. We discovered the genomic diversity among bone-only metastatic prostate cancer, hepatically metastatic prostate cancer and pulmonarily metastatic prostate cancer without liver involvement. Our findings shed new light on the heterogenous prognosis in visceral metastases and hint at potential therapeutic targets in both hepatically metastatic prostate cancer and pulmonarily metastatic prostate cancer without liver involvement.

Comparative Analysis of Genomic Alterations across Castration Sensitive and Castration Resistant Prostate Cancer via Circulating Tumor DNA Sequencing.

PURPOSE: To explore the genomic profiles of Chinese patients with castration sensitive prostate cancer and those with metastatic castration resistant prostate cancer via germline and circulating tumor DNA sequencing. MATERIALS AND METHODS: A hybridization capture based next-generation sequencing assay was used to identify germline and somatic alterations in 50 genes including androgen receptor pathway genes, DNA damage repair pathway genes, TP53 and RB1. RESULTS: We successfully sequenced DNA from 396 blood samples and 32 matched tumor tissue samples from 396 patients. We observed a similar frequency of deleterious germline alterations between patients with castration sensitive prostate cancer and metastatic castration resistant prostate cancer (8.9% vs 9.8%, p >0.05). There was a high consistency (90.9%) between metastatic tumor tissue and matched circulating tumor DNA. Among patients who were circulating tumor DNA positive we observed significantly higher alteration frequencies of CDK12 (27.2% vs 6.4%, p <0.001) and FOXA1 (36.8% vs 15.3%, p <0.001) in our metastatic castration resistant prostate cancer cohort compared with the SU2C-PCF (Stand Up to Cancer-Prostate Cancer Foundation) cohort. Alteration frequencies of DNA damage repair pathway genes (66.7% vs 41.5%, p=0.015) and androgen receptor pathway genes (71.9% vs 48.8%, p=0.018) in patients with metastatic castration resistant prostate cancer were higher than in patients with de novo metastatic castration sensitive prostate cancer. Androgen receptor alteration was selectively enriched in metastatic castration resistant prostate cancer. CONCLUSIONS: Through genomic profiling of prostate cancer across clinical states we identified a similar frequency of deleterious germline alterations between patients with castration sensitive prostate cancer and metastatic castration resistant prostate cancer. We explored the genomic diversity of androgen receptor and DNA damage repair pathway genes between patients with metastatic castration sensitive prostate cancer and metastatic castration resistant prostate cancer. Higher alteration frequencies of CDK12 and FOXA1 were observed in our metastatic castration resistant prostate cancer cohort than in the SU2C-PCF cohort. Our findings support the view that circulating tumor DNA sequencing could guide clinical treatment for metastatic prostate cancer.

Distinct Response to Platinum-Based Chemotherapy among Patients with Metastatic Castration-Resistant Prostate Cancer Harboring Alterations in Genes Involved in Homologous Recombination.

PURPOSE: We aimed to explore the association between genomic status and clinical outcome of platinum-based chemotherapy among patients with metastatic castration-resistant prostate cancer (mCRPC). MATERIALS AND METHODS: We conducted a retrospective study of 55 patients with mCRPC who received platinum-based chemotherapy after the progression to docetaxel chemotherapy and underwent genomic profiling of 14 homologous recombination (HR) pathway genes. Progression-free survival (PFS) was analyzed using the Kaplan-Meier method. RESULTS: Of 55 patients, 23 harbored genomic defects in HR pathway genes. Median prostate specific antigen (PSA)-PFS for the HR defect group was 6.7 months compared with 2.6 months for the no HR defect group (p=0.001). The patients harboring somatic HR defect displayed shorter PSA-PFS than those harboring germline HR defect (4.5 months vs not available; p=0.066). The PSA50 (patients who survived for 12 weeks and had a PSA decline over 50% from baseline) response rate displayed higher in patients harboring BRCA2 or ATM defect (6/8, 75.0%) than in those harboring CDK12 defect (2/9, 22.2%; p=0.06). Patients harboring BRCA2 or ATM defect displayed prolonged PSA-PFS, compared with those harboring CDK12 defect and those harboring other HR defect (p=0.038). In multivariate Cox regression analysis, HR defect and BRCA2 or ATM defect were independent significant factors associated with superior PAS-PFS to platinum-based chemotherapy. CONCLUSIONS: The patients with mCRPC harboring alterations in different HR genes displayed distinct response to platinum-based chemotherapy. Patients with mCRPC harboring genomic defects in crucial HR genes either in the germline or somatic, especially BRCA2 and ATM, might experience superior outcomes to platinum-based chemotherapy, compared with those harboring CDK12 defect.