Background
This study aims to tackle the lack of freshwater ecotoxicological effect factors (EFs) crucial for determining freshwater ecotoxicity characterization factors (CFs) using the widely ...accepted scientific consensus USEtox model for ecotoxicity impact characterization. The objectives are: (1) to offer a collection of experimental EFs to support USEtox ecotoxicity characterization factor computations and (2) to contrast ecotoxicity data produced by various quantitative structure–activity relationship (QSAR) models against experimental data.
Results
Experimental ecotoxicity data were gathered from the REACH database and CompTox Version 2.1.1, which includes toxicity information from ToxValDB v9.4. QSAR-driven ecotoxicity data were extracted from ECOSAR v1.11 and T.E.S.T. v5.1.2. The experimental and estimated data underwent a harmonization process to ensure consistency. Subsequently, aquatic ecotoxicological EFs were determined. The merged REACH and CompTox databases list EFs for 11,295 substances, each identified by a unique CAS number. Among these, the USEtox database already catalogs 2426 substances with freshwater ecotoxicological EFs. This study expanded on that by calculating EFs for an additional 8869 substances. Using estimated data, EFs were determined for 6029 chemicals based on ECOSAR data and 6762 chemicals using TEST data.
Conclusions
This study calculated EFs for an additional 8869 substances, thereby broadening their inclusion in LCA evaluations. When integrated with the USEtox EFs database, this research encompasses 11,368 chemicals. The high correlation observed between experimental EFs and those in the USEtox database lends significant confidence to the calculations for chemicals not listed in USEtox. Conversely, the low correlation between estimated EFs and those in USEtox suggests limited confidence in calculations based on estimated data. Furthermore, the disparity in correlations between EFs calculated using ECOSAR and TEST indicates that different QSARs can yield varied results. This discrepancy underscores the need for caution when relying on estimated data. Given that EFs are contingent on data availability, it is imperative to periodically update EFs as new data emerges.
Treatment options for advanced thyroid cancer refractory to standard therapies are limited. The safety and efficacy of pembrolizumab were evaluated in patients with advanced differentiated thyroid ...cancer expressing programmed death ligand 1 (PD-L1).
Patients with advanced thyroid cancer were enrolled in the nonrandomized, phase Ib KEYNOTE-028 trial conducted to evaluate safety and antitumor activity of the anti-programmed death 1 (PD-1) antibody pembrolizumab in advanced solid tumors. Key eligibility criteria were advanced papillary or follicular thyroid cancer, failure of standard therapy, and PD-L1 expression in tumor or stroma cells (assessed by immunohistochemistry). Pembrolizumab 10 mg/kg was administered every 2 weeks up to 24 months or until confirmed progression or intolerable toxicity. The primary endpoint was objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors, version 1.1.
Twenty-two patients were enrolled: median age was 61 years; 59% were women; and 68% had papillary carcinoma. Median follow-up was 31 months (range, 7-34 months). Treatment-related adverse events were observed in 18 (82%) patients; those occurring in ≥15% of patients were diarrhea (n = 7) and fatigue (n = 4). One grade ≥ 3 treatment-related adverse event occurred (colitis, grade 3); no treatment-related discontinuations or deaths occurred. Two patients had confirmed partial response, for an ORR of 9% (95% confidence interval CI, 1-29%); response duration was 8 and 20 months. Median progression-free survival was 7 months (95% CI, 2-14 months); median overall survival was not reached (95% CI, 22 months to not reached).
Results of this phase Ib proof-of-concept study suggest that pembrolizumab has a manageable safety profile and demonstrate evidence of antitumor activity in advanced differentiated thyroid cancer in a minority of patients treated. Further analyses are necessary to confirm these findings.
Clinicaltrials.gov identifier: NCT02054806 . Registered 4 February 2014.
Opioid overdose death rates are increasing for adults aged 55 and older, with especially high rates in large urban areas. In parallel, admissions to treatment programs for older adults using illicit ...substances are increasing as well. Despite these trends, there is a lack of information about older adults who use non-medical opioids (NMO) and even less knowledge about their health and service encounters. Conducted in Chicago, Illinois, this qualitative study explores the perspectives of health care and harm reduction service providers who work with older adults using non-medical opioids.
The study used snowball sampling to locate participants with expertise in working with older adults who use non-medical opioids. In total, we conducted 26 semi-structured interviews from September 2021-August 2022. We explored questions regarding participants' perceptions of older adult opioid use patterns, comorbidities, and involvement in harm reduction outreach and opioid use disorder treatment.
Many of the providers we interviewed consider older adults who use NMO as a distinct population that employ unique use behaviors with the intent to protect them from opioid overdose. However, these same unique behaviors may potentiate their risk for overdose in today's climate. Providers report initial encounters that are not care seeking for opioid use and primarily oriented around health conditions. Older adults who use non-medical opioids are seen as complex patients due to the need to diagnostically untangle symptoms of substance use from co-morbidities and conditions associated with aging. Treatment for this population is also viewed as complicated due to the interactions between aging, comorbidities, and substance use. Providers also noted that older adults who use NMO have use behaviors that make them less visible to outreach and treatment service providers, potentially putting them at increased risk for overdose and health conditions associated with opioid use.
Findings from this study are intended to inform future research on care provision for older adults who use non-medical opioids and may be especially applicable to large urban reas with histories of opioid use dating back to earlier drug epidemics of the 1970s, 1980s, and 1990s.
ZEN-3694 is a bromodomain extraterminal inhibitor (BETi) with activity in androgen-signaling inhibitor (ASI)-resistant models. The safety and efficacy of ZEN-3694 plus enzalutamide was evaluated in a ...phase Ib/IIa study in metastatic castration-resistant prostate cancer (mCRPC).
Patients had progressive mCRPC with prior resistance to abiraterone and/or enzalutamide. 3+3 dose escalation was followed by dose expansion in parallel cohorts (ZEN-3694 at 48 and 96 mg orally once daily, respectively).
Seventy-five patients were enrolled (
= 26 and 14 in dose expansion at low- and high-dose ZEN-3694, respectively). Thirty (40.0%) patients were resistant to abiraterone, 34 (45.3%) to enzalutamide, and 11 (14.7%) to both. ZEN-3694 dosing ranged from 36 to 144 mg daily without reaching an MTD. Fourteen patients (18.7%) experienced grade ≥3 toxicities, including three patients with grade 3 thrombocytopenia (4%). An exposure-dependent decrease in whole-blood RNA expression of BETi targets was observed (up to fourfold mean difference at 4 hours post-ZEN-3694 dose;
≤ 0.0001). The median radiographic progression-free survival (rPFS) was 9.0 months 95% confidence interval (CI), 4.6-12.9 and composite median radiographic or clinical progression-free survival (PFS) was 5.5 months (95% CI, 4.0-7.8). Median duration of treatment was 3.5 months (range, 0-34.7+). Lower androgen receptor (AR) transcriptional activity in baseline tumor biopsies was associated with longer rPFS (median rPFS 10.4 vs. 4.3 months).
ZEN-3694 plus enzalutamide demonstrated acceptable tolerability and potential efficacy in patients with ASI-resistant mCRPC. Further prospective study is warranted including in mCRPC harboring low AR transcriptional activity.
US policymakers are debating whether to expand the Medicare program by lowering the age of eligibility. The goal of this study was to determine the association of Medicare eligibility and enrollment ...with healthcare access, affordability, and financial strain from medical bills in a contemporary population of low- and higher-income adults in the US.
We used cross-sectional data from the National Health Interview Survey (2019) to examine the association of Medicare eligibility and enrollment with outcomes by income status using a local randomization-based regression discontinuity approach. After weighting to account for survey sampling, the low-income group consisted of 1,660,188 adults age 64 years and 1,488,875 adults age 66 years, with similar baseline characteristics, including distribution of sex (59.2% versus 59.7% female) and education (10.8% versus 12.5% with bachelor's degree or higher). The higher-income group consisted of 2,110,995 adults age 64 years and 2,167,676 adults age 66 years, with similar distribution of baseline characteristics, including sex (40.0% versus 49.4% female) and education (41.0% versus 41.6%). The share of adults age 64 versus 66 years enrolled in Medicare differed within low-income (27.6% versus 87.8%, p < 0.001) and higher-income groups (8.0% versus 85.9%, p < 0.001). Medicare eligibility at 65 years was associated with a decreases in the percentage of low-income adults who delayed (14.7% to 6.2%; -8.5% 95% CI, -14.7%, -2.4%, P = 0.007) or avoided medical care (15.5% to 5.9%; -9.6% -15.9%, -3.2%, P = 0.003) due to costs, and a larger decrease in the percentage who were worried about (66.5% to 51.1%; -15.4% -25.4%, -5.4%, P = 0.003) or had problems (33.9% to 20.6%; -13.3% -23.0%, -3.6%, P = 0.007) paying medical bills. In contrast, there were no significant associations between Medicare eligibility and measures of cost-related barriers to medication use. For higher-income adults, there was a large decrease in worrying about paying medical bills (40.5% to 27.5%; -13.0% -21.4%, -4.5%, P = 0.003), a more modest decrease in avoiding medical care due to cost (3.5% to 0.6%; -2.9% -5.3%, -0.5%, P = 0.02), and no significant association between eligibility and other measures of healthcare access and affordability. All estimates were stronger when examining the association of Medicare enrollment with outcomes for low and higher-income adults. Additional analyses that adjusted for clinical comorbidities and employment status were largely consistent with the main findings, as were analyses stratified by levels of educational attainment. Study limitations include the assumption adults age 64 and 66 would have similar outcomes if both groups were eligible for Medicare or if eligibility were withheld from both.
Medicare eligibility and enrollment at age 65 years were associated with improvements in healthcare access, affordability, and financial strain in low-income adults and, to a lesser extent, in higher-income adults. Our findings provide evidence that lowering the age of eligibility for Medicare may improve health inequities in the US.
Purpose The prevalence and features of treatment-emergent small-cell neuroendocrine prostate cancer (t-SCNC) are not well characterized in the era of modern androgen receptor (AR)-targeting therapy. ...We sought to characterize the clinical and genomic features of t-SCNC in a multi-institutional prospective study. Methods Patients with progressive, metastatic castration-resistant prostate cancer (mCRPC) underwent metastatic tumor biopsy and were followed for survival. Metastatic biopsy specimens underwent independent, blinded pathology review along with RNA/DNA sequencing. Results A total of 202 consecutive patients were enrolled. One hundred forty-eight (73%) had prior disease progression on abiraterone and/or enzalutamide. The biopsy evaluable rate was 79%. The overall incidence of t-SCNC detection was 17%. AR amplification and protein expression were present in 67% and 75%, respectively, of t-SCNC biopsy specimens. t-SCNC was detected at similar proportions in bone, node, and visceral organ biopsy specimens. Genomic alterations in the DNA repair pathway were nearly mutually exclusive with t-SCNC differentiation ( P = .035). Detection of t-SCNC was associated with shortened overall survival among patients with prior AR-targeting therapy for mCRPC (hazard ratio, 2.02; 95% CI, 1.07 to 3.82). Unsupervised hierarchical clustering of the transcriptome identified a small-cell-like cluster that further enriched for adverse survival outcomes (hazard ratio, 3.00; 95% CI, 1.25 to 7.19). A t-SCNC transcriptional signature was developed and validated in multiple external data sets with > 90% accuracy. Multiple transcriptional regulators of t-SCNC were identified, including the pancreatic neuroendocrine marker PDX1. Conclusion t-SCNC is present in nearly one fifth of patients with mCRPC and is associated with shortened survival. The near-mutual exclusivity with DNA repair alterations suggests t-SCNC may be a distinct subset of mCRPC. Transcriptional profiling facilitates the identification of t-SCNC and novel therapeutic targets.
High lipid concentrations are a modifiable risk factor for cardiovascular disease. Little is known about how population-level lipid concentrations, as well as trends in lipid control, have changed ...over the past decade among US adults.
To determine whether lipid concentrations and rates of lipid control changed among US adults and whether these trends differed by sex and race and ethnicity, from 2007 to 2018.
Serial cross-sectional analysis of 33 040 US adults aged 20 years or older, weighted to be nationally representative, from the National Health and Nutrition Examination Surveys (2007-2008 to 2017-2018).
Lipid concentrations among US adults and rates of lipid control among adults receiving statin therapy. Lipid control was defined as a total cholesterol concentration of 200 mg/dL or less.
The mean age of the study population was 47.4 years, and 51.4% were women; of the 33 040 participants, 12.0% were non-Hispanic Black; 10.3%, Mexican American; 6.4%, other Hispanic American; 62.7%, non-Hispanic White; and 8.5%, other race and ethnicities (including non-Hispanic Asian. Among all US adults, age-adjusted total cholesterol improved significantly in the overall population from 197 mg/dL in 2007-2008 to 189 mg/dL in 2017-2018 (difference, -8.6 mg/dL 95% CI, -12.2 to -4.9 mg/dL; P for trend <.001), with similar patterns for men and women. Black, Mexican American, other Hispanic, and White adults experienced significant improvements in total cholesterol, but no significant change was observed for Asian adults. Among adults receiving statin therapy, age-adjusted lipid control rates did not significantly change from 78.5% in 2007-2008 to 79.5% in 2017-2018 (difference, 1.1% 95% CI, -3.7% to 5.8%; P for trend = .27), and these patterns were similar for men and women. Across all racial and ethnic groups, only Mexican Americans experienced a significant improvement in age-adjusted lipid control (P for trend = .008). In 2015-2018, age-adjusted rates of lipid control were significantly lower for women than for men (OR, 0.54 95% CI, 0.40 to 0.72). In addition, when compared with White adults, rates of lipid control while taking statins were significantly lower among Black adults (OR, 0.66 95% CI, 0.47 to 0.94) and other Hispanic adults (OR, 0.59 95% CI, 0.37 to 0.95); no significant differences were observed for other racial and ethnic groups.
In this serial cross-sectional study, lipid concentrations improved in the US adult population from 2007-2008 through 2017-2018. These patterns were observed across all racial and ethnic subgroups, with the exception of non-Hispanic Asian adults.
Prostate cancer is the most commonly diagnosed neoplasm in American men. Although existing biomarkers may detect localized prostate cancer, additional strategies are necessary for improving detection ...and identifying aggressive disease that may require further intervention. One promising, minimally invasive biomarker is cell-free DNA (cfDNA), which consist of short DNA fragments released into circulation by dying or lysed cells that may reflect underlying cancer. Here we investigated whether differences in cfDNA concentration and cfDNA fragment size could improve the sensitivity for detecting more advanced and aggressive prostate cancer. This study included 268 individuals: 34 healthy controls, 112 men with localized prostate cancer who underwent radical prostatectomy (RP), and 122 men with metastatic castration-resistant prostate cancer (mCRPC). Plasma cfDNA concentration and fragment size were quantified with the Qubit 3.0 and the 2100 Bioanalyzer. The potential relationship between cfDNA concentration or fragment size and localized or mCRPC prostate cancer was evaluated with descriptive statistics, logistic regression, and area under the curve analysis with cross-validation. Plasma cfDNA concentrations were elevated in mCRPC patients in comparison to localized disease (OR
= 1.34, P = 0.027) or to being a control (OR
= 1.69, P = 0.034). Decreased average fragment size was associated with an increased risk of localized disease compared to controls (OR
= 0.77, P = 0.0008). This study suggests that while cfDNA concentration can identify mCRPC patients, it is unable to distinguish between healthy individuals and patients with localized prostate cancer. In addition to PSA, average cfDNA fragment size may be an alternative that can differentiate between healthy individuals and those with localized disease, but the low sensitivity and specificity results in an imperfect diagnostic marker. While quantification of cfDNA may provide a quick, cost-effective approach to help guide treatment decisions in advanced disease, its use is limited in the setting of localized prostate cancer.
Abstract Background Germline mutations in DNA repair genes were recently reported in 8–12% of patients with metastatic castration-resistant prostate cancer (mCRPC). It is unknown whether these ...mutations associate with differential response to androgen receptor (AR)-directed therapy. Objective To determine the clinical response of mCRPC patients with germline DNA repair defects to AR-directed therapies and to establish whether biallelic DNA repair gene loss is detectable in matched circulating tumor DNA (ctDNA). Design, setting, and participants We recruited 319 mCRPC patients and performed targeted germline sequencing of 22 DNA repair genes. In patients with deleterious germline mutations, plasma cell-free DNA was also sequenced. Outcome measurements and statistical analysis Prostate-specific antigen response and progression were assessed in relation to initial androgen deprivation therapy (ADT) and subsequent therapy for mCRPC using Kaplan–Meier analysis. Results and limitations Of the 319 patients, 24 (7.5%) had deleterious germline mutations, with BRCA2 ( n = 16) being the most frequent. Patients ( n = 22) with mutations in genes linked to homologous recombination were heterogeneous at initial presentation but, after starting ADT, progressed to mCRPC with a median time of 11.8 mo (95% confidence interval CI 5.1–18.4). The median time to prostate-specific antigen progression on first-line AR-targeted therapy in the mCRPC setting was 3.3 mo (95% CI 2.7-3.9). Ten out of 11 evaluable patients with germline BRCA2 mutations had somatic deletion of the intact allele in ctDNA. A limitation of this study is absence of a formal control cohort for comparison of clinical outcomes. Conclusions Patients with mCRPC who have germline DNA repair defects exhibit attenuated responses to AR-targeted therapy. Biallelic gene loss was robustly detected in ctDNA, suggesting that this patient subset could be prioritized for therapies exploiting defective DNA repair using a liquid biopsy. Patient summary Patients with metastatic prostate cancer and germline DNA repair defects exhibit a poor response to standard hormonal therapies, but may be prioritized for potentially more effective therapies using a blood test.
Purpose of Review
Prostate cancer (PCa) is the most frequently diagnosed malignancy in men in developed countries and a leading cause of cancer death worldwide. Effective methods for diagnosing and ...staging PCa are necessary to guide treatment options in a personalized manner. The purpose of this paper is to review recent advances in molecular imaging and therapeutics and their expanding role in imaging and treating PCa.
Recent Findings
Compared with conventional imaging, PSMA PET has proven more accurate at detecting PCa in patients with newly diagnosed PCa or biochemically recurrent PCa. PSMA PET can also induce management changes in patients due to its superior accuracy in detecting metastatic disease. Further research is necessary to understand the appropriate role of PSMA PET in patients with known metastatic PCa and the impact on clinical outcomes in patients who undergo treatment planning using findings from PSMA PET.
Summary
We review the role of molecular imaging in primary and biochemically recurrent PCa. We find that molecular imaging is effective in detecting PCa and may lead to management changes.
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