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•Measurement of silicon segregation in solution strengthened ferritic ductile iron.•Micropillar compression tests and trace analysis.•Determination of CRSS as a function of the ...silicon content in the ferrite matrix.•Comparison of the measured CRSS with macroscopic yield limits under tension and compression.
Solid solution strengthened ferritic ductile iron (SSFDI) exhibits improved mechanical properties compared to conventional ductile cast iron (DCI) grades, however, its potential widespread application is hindered by unpredictable brittle fracture which might be attributed to microstructural silicon segregation and associated superstructure formation. The aim of the present study is therefore to deepen the understanding on the effect of local silicon segregation on the mechanical properties of SSFDI, which is crucial especially for the common applications of DCI in cyclically loaded structures. Micropillar compression tests were carried out on three different casts to investigate the solution strengthening effect of silicon in the ferritic matrix. An almost perfect linear relationship between critical resolved shear stress (CRSS) and global silicon content was found. It was also found that the variation of CRSS with silicon content corresponds well to the variation of the macroscopic yield limits (under tension and compression) with global silicon content of different SSFDI alloys. This indicates that the ferritic matrix dominates the yield limit of the DCI alloys investigated in this study, while the morphology of the graphite nodules plays a minor role under monotonic loading conditions.
Rainwater chemistry of extreme rain events is not well characterized. This is despite an increasing trend in intensity and frequency of extreme events and the potential excess loading of elements to ...ecosystems that can rival annual loading. Thus, an assessment of the loading imposed by hurricane/tropical storm (H/TS) can be valuable for future resiliency strategies. Here the chemical characteristics of H/TS and normal rain (NR) in the US from 2008 to 2019 were determined from available National Atmospheric Deposition Program (NADP) data by correlating NOAA storm tracks with NADP rain collection locations. It found the average pH of H/TS (5.37) was slightly higher (p < 0.05) than that of NR (5.12). On average, H/TS events deposited 14% of rain volume during hurricane season (May to October) at affected collection sites with a maximum contribution reaching 47%. H/TS events contributed a mean of 12% of Ca2+, 22% of Mg2+, 18% of K+, 25% of Na+, 7% of NH4+, 6% of NO3−, 25% of Cl− and 11% of SO42− during hurricane season with max loading of 77%, 62%, 94%, 65%, 39%, 34%, 64% and 60%, respectively, which can lead to ecosystems exceeding ion-specific critical loads. Four potential sources (i.e., marine, soil dust, agriculture and industry/fossil fuel) were indicated by PCA. The positive matrix factorization (PMF) suggested Mg2+, Na+ and Cl− were primarily marine-originated in both event types, while 36% more sea-salt Ca2+ and 33% more sea-salt SO42− were deposited during H/TS. Agriculture and industry/fossil fuel were the main sources of NH4+ and NO3−, respectively, in both rain event types. However the NH4+ contribution from industry/fossil fuel increased by 13% during H/TS indicating a potential vehicle source associated with emergency evacuations. This work provides a comprehensive assessment of the rainwater chemistry of H/TS and insight to expected ecosystem loading for future extreme events.
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•H/TS can contribute large rain amount and ion depositions within hours.•The large ion deposition can help exceed potential critical load of ecosystem.•Mg2+, Ca2+ and SO42− are more correlated with Na+ and Cl− during H/TS•H/TS can entrain more marine materials and deposit more sea-salt ions.•An increased NH4+ emission from industry/fossil fuel was observed during H/TS.
Randomised trials have investigated various androgen deprivation therapy (ADT) intensification strategies in men receiving radiotherapy for the treatment of prostate cancer. This individual patient ...data meta-analysis of relevant randomised trials aimed to quantify the benefit of these interventions in aggregate and in clinically relevant subgroups.
For this meta-analysis, we performed a systematic literature search in MEDLINE, Embase, trial registries, the Web of Science, Scopus, and conference proceedings to identify trials with results published in English between Jan 1, 1962, and Dec 30, 2020. Multicentre randomised trials were eligible if they evaluated the use or prolongation of ADT (or both) in men with localised prostate cancer receiving definitive radiotherapy, reported or collected distant metastasis and survival data, and used ADT for a protocol-defined finite duration. The Meta-Analysis of Randomized trials in Cancer of the Prostate (MARCAP) Consortium was accessed to obtain individual patient data from randomised trials. The primary outcome was metastasis-free survival. Hazard ratios (HRs) were obtained through stratified Cox models for ADT use (radiotherapy alone vs radiotherapy plus ADT), neoadjuvant ADT extension (ie, extension of total ADT duration in the neoadjuvant setting from 3–4 months to 6–9 months), and adjuvant ADT prolongation (ie, prolongation of total ADT duration in the adjuvant setting from 4–6 months to 18–36 months). Formal interaction tests between interventions and metastasis-free survival were done for prespecified subgroups defined by age, National Comprehensive Cancer Network (NCCN) risk group, and radiotherapy dose. This meta-analysis is registered with PROSPERO, CRD42021236855.
Our search returned 12 eligible trials that provided individual patient data (10 853 patients) with a median follow-up of 11·4 years (IQR 9·0–15·0). The addition of ADT to radiotherapy significantly improved metastasis-free survival (HR 0·83 95% CI 0·77–0·89, p<0·0001), as did adjuvant ADT prolongation (0·84 0·78–0·91, p<0·0001), but neoadjuvant ADT extension did not (0·95 0·83–1·09, p=0·50). Treatment effects were similar irrespective of radiotherapy dose, patient age, or NCCN risk group.
Our findings provide the strongest level of evidence so far to the magnitude of the benefit of ADT treatment intensification with radiotherapy for men with localised prostate cancer. Adding ADT and prolonging the portion of ADT that follows radiotherapy is associated with improved metastasis-free survival in men, regardless of risk group, age, and radiotherapy dose delivered; however, the magnitude of the benefit could vary and shared decision making with patients is recommended.
University Hospitals Seidman Cancer Center, Prostate Cancer Foundation, and the American Society for Radiation Oncology.
We provide the strongest evidence to date that local failure is an independent prognosticator of outcomes in high- and intermediate-risk prostate cancer patients treated with definitive radiation ...therapy. Distant metastasis predominantly develops from a clinical relapse-free state; however, a second wave of distant metastasis occurs subsequent to local failure, albeit less commonly.
The prognostic importance of local failure after definitive radiotherapy (RT) in National Comprehensive Cancer Network intermediate- and high-risk prostate cancer (PCa) patients remains unclear.
To evaluate the prognostic impact of local failure and the kinetics of distant metastasis following RT.
A pooled analysis was performed on individual patient data of 12 533 PCa (6288 high-risk and 6245 intermediate-risk) patients enrolled in 18 randomized trials (conducted between 1985 and 2015) within the Meta-analysis of Randomized Trials in Cancer of the Prostate Consortium. Multivariable Cox proportional hazard (PH) models were developed to evaluate the relationship between overall survival (OS), PCa-specific survival (PCSS), distant metastasis-free survival (DMFS), and local failure as a time-dependent covariate. Markov PH models were developed to evaluate the impact of specific transition states.
The median follow-up was 11 yr. There were 795 (13%) local failure events and 1288 (21%) distant metastases for high-risk patients and 449 (7.2%) and 451 (7.2%) for intermediate-risk patients, respectively. For both groups, 81% of distant metastases developed from a clinically relapse-free state (cRF state). Local failure was significantly associated with OS (hazard ratio HR 1.17, 95% confidence interval CI 1.06–1.30), PCSS (HR 2.02, 95% CI 1.75–2.33), and DMFS (HR 1.94, 95% CI 1.75–2.15, p < 0.01 for all) in high-risk patients. Local failure was also significantly associated with DMFS (HR 1.57, 95% CI 1.36–1.81) but not with OS in intermediate-risk patients. Patients without local failure had a significantly lower HR of transitioning to a PCa-specific death state than those who had local failure (HR 0.32, 95% CI 0.21–0.50, p < 0.001). At later time points, more distant metastases emerged after a local failure event for both groups.
Local failure is an independent prognosticator of OS, PCSS, and DMFS in high-risk and of DMFS in intermediate-risk PCa. Distant metastasis predominantly developed from the cRF state, underscoring the importance of addressing occult microscopic disease. However a “second wave” of distant metastases occurs subsequent to local failure events, and optimization of local control may reduce the risk of distant metastasis.
Among men receiving definitive radiation therapy for high- and intermediate-risk prostate cancer, about 10% experience local recurrence, and they are at significantly increased risks of further disease progression. About 80% of patients who develop distant metastasis do not have a detectable local recurrence preceding it.
Mitigating ammonia (NH3) emissions is a significant challenge, given its well-recognized role in the troposphere, contributing to secondary particle formation and impacting acid rain. The difficulty ...arises from the highly uncertain attribution of atmospheric NH3 to specific emission sources, especially when accounting for diverse environments and varying spatial and temporal scales. In this study, we established a refined δ15N fingerprint for eight emission sources, including three previously overlooked sources of potential importance. We applied this approach in a year-long case study conducted in urban and rural sites located only 40 km apart in the Shandong Peninsula, North China Plain. Our findings highlight that although atmospheric NH3 concentrations and seasonal trends exhibited similarities, their isotopic compositions revealed significant distinctions in the primary NH3 sources. In rural areas, although agriculture emerged as the dominant emission source (64.2 ± 19.5%), a previously underestimated household stove source also played a considerably greater role, particularly during cold seasons (36.5 ± 12.5%). In urban areas, industry and traffic (33.5 ± 15.6%) and, surprisingly, sewage treatment (27.7 ± 11.3%) associated with high population density were identified as the major contributors. Given the relatively short lifetime of atmospheric NH3, our findings highlight the significance of the isotope approach in offering a more comprehensive understanding of localized and seasonal influences of NH3 sources compared to emissions inventories. The refined isotopic fingerprint proves to be an effective tool in distinguishing source contributions across spatial and seasonal scales, thereby providing valuable insights for the development of emission mitigation policies aimed at addressing the increasing NH3 burden on the local atmosphere.
We provide the strongest evidence to date for the combined benefit of radiotherapy (RT) dose escalation and androgen deprivation therapy (ADT) use/adjuvant ADT prolongation in optimizing biochemical ...control–based outcomes. However, RT dose escalation is unlikely to improve metastasis-free survival, although ADT use and adjuvant ADT prolongation consistently will.
The relative benefits of radiotherapy (RT) dose escalation and the addition of short-term or long-term androgen deprivation therapy (STADT or LTADT) in the treatment of prostate cancer are unknown.
To perform a network meta-analysis (NMA) of relevant randomized trials to compare the relative benefits of RT dose escalation ± STADT or LTADT.
An NMA of individual patient data from 13 multicenter randomized trials was carried out for a total of 11862 patients. Patients received one of the six permutations of low-dose RT (64 to <74 Gy) ± STADT or LTADT, high-dose RT (≥74 Gy), or high-dose RT ± STADT or LTADT.
Metastasis-free survival (MFS) was the primary endpoint. Frequentist and Bayesian NMAs were performed to rank the various treatment strategies by MFS and biochemical recurrence–free survival (BCRFS).
Median follow-up was 8.8 yr (interquartile range 5.7–11.5). The greatest relative improvement in outcomes was seen for addition of LTADT, irrespective of RT dose, followed by addition of STADT, irrespective of RT dose. RT dose escalation did not improve MFS either in the absence of ADT (hazard ratio HR 0.97, 95% confidence interval CI 0.80–1.18) or with STADT (HR 0.99, 95% CI 0.8–1.23) or LTADT (HR 0.94, 95% CI 0.65–1.37). According to P-score ranking and rankogram analysis, high-dose RT + LTADT was the optimal treatment strategy for both BCRFS and longer-term outcomes.
Conventionally escalated RT up to 79.2 Gy, alone or in the presence of ADT, does not improve MFS, while addition of STADT or LTADT to RT alone, regardless of RT dose, consistently improves MFS. RT dose escalation does provide a high probability of improving BCRFS and, provided it can be delivered without compromising quality of life, may represent the optimal treatment strategy when used in conjunction with ADT.
Using a higher radiotherapy dose when treating prostate cancer does not reduce the chance of developing metastases or death, but it does reduce the chance of having a rise in prostate-specific antigen (PSA) signifying recurrence of cancer. Androgen deprivation therapy improves all outcomes. A safe increase in radiotherapy dose in conjunction with androgen deprivation therapy may be the optimal treatment.
PURPOSE
The surrogacy of biochemical recurrence (BCR) for overall survival (OS) in localized prostate cancer remains controversial. Herein, we evaluate the surrogacy of BCR using different surrogacy ...analytic methods.
MATERIALS AND METHODS
Individual patient data from 11 trials evaluating radiotherapy dose escalation, androgen deprivation therapy (ADT) use, and ADT prolongation were obtained. Surrogate candidacy was assessed using the Prentice criteria (including landmark analyses) and the two-stage meta-analytic approach (estimating Kendall's tau and the R
2
). Biochemical recurrence-free survival (BCRFS, time from random assignment to BCR or any death) and time to BCR (TTBCR, time from random assignment to BCR or cancer-specific deaths censoring for noncancer-related deaths) were assessed.
RESULTS
Overall, 10,741 patients were included. Dose escalation, addition of short-term ADT, and prolongation of ADT duration significantly improved BCR (hazard ratio HR, 0.71 95% CI, 0.63 to 0.79; HR, 0.53 95% CI, 0.48 to 0.59; and HR, 0.54 95% CI, 0.48 to 0.61, respectively). Adding short-term ADT (HR, 0.91 95% CI, 0.84 to 0.99) and prolonging ADT (HR, 0.86 95% CI, 0.78 to 0.94) significantly improved OS, whereas dose escalation did not (HR, 0.98 95% CI, 0.87 to 1.11). BCR at 48 months was associated with inferior OS in all three groups (HR, 2.46 95% CI, 2.08 to 2.92; HR, 1.51 95% CI, 1.35 to 1.70; and HR, 2.31 95% CI, 2.04 to 2.61, respectively). However, after adjusting for BCR at 48 months, there was no significant treatment effect on OS (HR, 1.10 95% CI, 0.96 to 1.27; HR, 0.96 95% CI, 0.87 to 1.06 and 1.00 95% CI, 0.90 to 1.12, respectively). The patient-level correlation (Kendall's tau) for BCRFS and OS ranged between 0.59 and 0.69, and that for TTBCR and OS ranged between 0.23 and 0.41. The R
2
values for trial-level correlation of the treatment effect on BCRFS and TTBCR with that on OS were 0.563 and 0.160, respectively.
CONCLUSION
BCRFS and TTBCR are prognostic but failed to satisfy all surrogacy criteria. Strength of correlation was greater when noncancer-related deaths were considered events.
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Background: Event-free survival, a PSA-driven endpoint, was shown to not be surrogate endpoint for overall survival (OS) in the ICECAP two-stage meta-analytic approach. However, time to ...biochemical recurrence (TTBCR) in NRG/RTOG 9202 met Prentice criteria for surrogacy. We performed an individual patient data (IPD) meta-analysis of 11 randomized controlled trials evaluating RT dose escalation, ADT use, and adjuvant ADT prolongation to evaluate the surrogacy of time to BCR (TTBCR), censoring for non-prostate cancer deaths, using both approaches to evaluate surrogacy. Methods: This individual patient level meta-analysis was performed using data from the MARCAP consortium, and 11 radiotherapy trials were included. TTBCR was defined as time to developing a BCR or experiencing prostate cancer-specific mortality (PCSM), with censoring at time of other-cause death or loss to follow-up. Landmark analyses were used to test the Prentice criteria for surrogacy. For patient level correlation between TTBCR and OS, we applied a bivariate Copula model to estimate the Kendall’s τ. For trial level correlation of the treatment effect on TTBCR and true endpoints, a weighted linear regression model was applied between the effects of treatment (natural log of hazard ratio log-HR) on OS versus TTBCR using a weightage that was inverse variance of BCR log-HR estimate. Results: Based on Prentice criteria, BCR at the landmark time point of 48 months was associated with increased risk of mortality in trials that compared treatment intensification with adjuvant ADT prolongation (HR 2.18 95% CI 1.95-2.42), the addition of ADT (HR 1.38 1.25-1.54), and RT dose escalation (HR 2.12 1.83-2.46) on uni- and multi-variable analyses. At the patient level, there was a low to moderate level correlation between BCR and OS with Kendall’s τ of 0.34 and a R
2
of 0.55 for correlation of treatment effect on TTBCR and OS. At the trial level, there was a poor correlation between treatment effect on TTBCR and OS (R
2
=0.16). Conclusions: This IPD meta-analysis demonstrates that while BCR is prognostic, it is not a surrogate endpoint for OS in localized prostate cancer for patients treated with a diverse array of radiotherapeutic strategies. This highlights the importance of other cause mortality in prostate cancer. Our results highlight the differences in interpretability of Prentice criteria and the two-stage meta-analytic approach and suitability of endpoints for clinical trial design.
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