Next-generation sequencing (NGS) of circulating tumor DNA (ctDNA) supports blood-based genomic profiling but is not yet routinely implemented in the setting of a phase I trials clinic. TARGET is a ...molecular profiling program with the primary aim to match patients with a broad range of advanced cancers to early phase clinical trials on the basis of analysis of both somatic mutations and copy number alterations (CNA) across a 641 cancer-associated-gene panel in a single ctDNA assay. For the first 100 TARGET patients, ctDNA data showed good concordance with matched tumor and results were turned round within a clinically acceptable timeframe for Molecular Tumor Board (MTB) review. When a 2.5% variant allele frequency (VAF) threshold was applied, actionable mutations were identified in 41 of 100 patients, and 11 of these patients received a matched therapy. These data support the application of ctDNA in this early phase trial setting where broad genomic profiling of contemporaneous tumor material enhances patient stratification to novel therapies and provides a practical template for bringing routinely applied blood-based analyses to the clinic.
Malnutrition is a problem in advanced cancer, particularly ovarian cancer where malignant bowel obstruction (MBO) is a frequent complication. Parenteral nutrition is the only way these patients can ...received adequate nutrition and is a principal indication for palliative home parenteral nutrition (HPN). Giving HPN is contentious as it may increase the burden on patients. This study investigates patients' and family caregivers' experiences of HPN, alongside nutritional status and survival in patients with ovarian cancer and MBO.
This mixed methods study collected data on participant characteristics, clinical details and body composition using computed tomography (CT) combined with longitudinal in-depth interviews underpinned by phenomenological principles. The cohort comprised 38 women with ovarian cancer and inoperable MBO admitted (10/2016 to 12/ 2017) to a tertiary referral hospital. Longitudinal interviews (n = 57) were carried out with 20 women considered for HPN and 13 of their family caregivers.
Of the 38 women, 32 received parenteral nutrition (PN) in hospital and 17 were discharged on HPN. Nutritional status was poor with 31 of 33 women who had a CT scan having low muscle mass, although 10 were obese. Median overall survival from admission with MBO for all 38 women was 70 days (range 8-506) and for those 17 on HPN was 156 days (range 46-506). Women experienced HPN as one facet of their illness, but viewed it as a "lifeline" that allowed them to live outside hospital. Nevertheless, HPN treatment came with losses including erosion of normality through an impact on activities of daily living and dealing with the bureaucracy surrounding the process. Family caregivers coped but were often left in an emotionally vulnerable state.
Women and family caregivers reported that the inconvenience and disruption caused by HPN was worth the extended time they had at home.
Small cell lung cancer (SCLC) has a dismal prognosis. Circulating tumour cells (CTCs) can be used to generate CTC derived explants (CDX) for the study of SCLC biology and the development of novel ...therapeutics. We investigated whether there are demographic or clinical predictors of the success of CDX generation, and whether CDX models are representative of the SCLC patient population.
This was a single centre, retrospective analysis of SCLC patients who had participated in the CHEMORES Study. Paired blood samples were donated for CTC enumeration and CDX generation attempt at pre-treatment baseline, disease progression and intervening timepoints. Clinical and demographic data was collected from electronic records, and analysed for differences between patients whose samples did and did not generate a CDX.
231 paired blood samples were taken from 147 patients. 45 CDX were generated from 34 patients. CTC number was significantly higher in blood samples which successfully generated a CDX than those which didn’t, at both baseline (p=<0.0001) and progression (p = 0.0001). The group with successful blood samples had a poorer performance status (p = 0.0067), and a higher proportion of patients with chemorefractory disease (p = 0.0077). Both progression free survival (PFS) (p = 0.0132) and overall survival (p=< 0.0001) were significantly shorter for patients with successful samples.
Patients whose samples generate CDX models may have a higher disease burden and more aggressive disease. Thus, insights gained by study of SCLC CDX may have a significant impact, particularly in the SCLC subpopulation with the greatest clinical need.
Drilling for the International Continental Scientific Drilling Program (ICDP) Early Jurassic Earth System and Timescale project (JET) was undertaken between October 2020 and January 2021. The drill ...site is situated in a small-scale synformal basin of the latest Triassic to Early Jurassic age that formed above the major Permian–Triassic half-graben system of the Cheshire Basin. The borehole is located to recover an expanded and complete succession to complement the legacy core from the Llanbedr (Mochras Farm) borehole drilled through 1967–1969 on the edge of the Cardigan Bay Basin, North Wales. The overall aim of the project is to construct an astronomically calibrated integrated timescale for the Early Jurassic and to provide insights into the operation of the Early Jurassic Earth system. Core of Quaternary age cover and Early Jurassic mudstone was obtained from two shallow partially cored geotechnical holes (Prees 2A to 32.2 m below surface (m b.s.) and Prees 2B to 37.0 m b.s.) together with Early Jurassic and Late Triassic mudstone from the principal hole, Prees 2C, which was cored from 32.92 to 651.32 m (corrected core depth scale). Core recovery was 99.7 % for Prees 2C. The ages of the recovered stratigraphy range from the Late Triassic (probably Rhaetian) to the Early Jurassic, Early Pliensbachian (Ibex Ammonoid Chronozone). All ammonoid chronozones have been identified for the drilled Early Jurassic strata. The full lithological succession comprises the Branscombe Mudstone and Blue Anchor formations of the Mercia Mudstone Group, the Westbury and Lilstock formations of the Penarth Group, and the Redcar Mudstone Formation of the Lias Group. A distinct interval of siltstone is recognized within the Late Sinemurian of the Redcar Mudstone Formation, and the name “Prees Siltstone Member” is proposed. Depositional environments range from playa lake in the Late Triassic to distal offshore marine in the Early Jurassic. Initial datasets compiled from the core include radiography, natural gamma ray, density, magnetic susceptibility, and X-ray fluorescence (XRF). A full suite of downhole logs was also run. Intervals of organic carbon enrichment occur in the Rhaetian (Late Triassic) Westbury Formation and in the earliest Hettangian and earliest Pliensbachian strata of the Redcar Mudstone Formation, where up to 4 % total organic carbon (TOC) is recorded. Other parts of the succession are generally organic-lean, containing less than 1 % TOC. Carbon-isotope values from bulk organic matter have also been determined, initially at a resolution of ∼ 1 m, and these provide the basis for detailed correlation between the Prees 2 succession and adjacent boreholes and Global Stratotype Section and Point (GSSP) outcrops. Multiple complementary studies are currently underway and preliminary results promise an astronomically calibrated biostratigraphy, magnetostratigraphy, and chemostratigraphy for the combined Prees and Mochras successions as well as insights into the dynamics of background processes and major palaeo-environmental changes.
In a large, international cohort, men with indications for prostate biopsy have an increased risk of high-grade prostate cancer in the presence of a family history of prostate cancer, second-degree ...prostate cancer, and first-degree breast cancer, controlling for other risk factors. This risk did not vary based on prostate-specific antigen level, and having additional affected relatives conferred an increased risk of high-grade prostate cancer on biopsy.
The risk of high-grade prostate cancer, given a family history of cancer, has been described in the general population, but not among men selected for prostate biopsy in an international cohort.
To estimate the risk of high-grade prostate cancer on biopsy based on a family history of cancer.
This is a multicenter study of men undergoing prostate biopsy from 2006 to 2019, including 12 sites in North America and Europe. All sites recorded first-degree prostate cancer family histories; four included more detailed data on the number of affected relatives, second-degree relatives with prostate cancer, and breast cancer family history.
Multivariable logistic regressions evaluated odds of high-grade (Gleason grade group ≥2) prostate cancer. Separate models were fit for family history definitions, including first- and second-degree prostate cancer and breast cancer family histories.
A first-degree prostate cancer family history was available for 15 799 men, with a more detailed family history for 4617 (median age 65 yr, both cohorts). Adjusted odds of high-grade prostate cancer were 1.77 times greater (95% confidence interval CI 1.57−2.00, p < 0.001, risk ratio RR = 1.40) with first-degree prostate cancer, 1.38 (95% CI 1.07−1.77, p = 0.011, RR = 1.22) for second-degree prostate cancer, and 1.30 (95% CI 1.01−1.67, p = 0.040, RR = 1.18) for first-degree breast cancer family histories. Interaction terms revealed that the effect of a family history did not differ based on prostate-specific antigen but differed based on age. This study is limited by missing data on race and prior negative biopsy.
Men with indications for biopsy and a family history of prostate or breast cancer can be counseled that they have a moderately increased risk of high-grade prostate cancer, independent of other risk factors.
In a large international series of men selected for prostate biopsy, finding a high-grade prostate cancer was more likely in men with a family history of prostate or breast cancer.
To assess whether adding prostate volume to the kallikrein panel improves discrimination for ISUP Grade Group 2 or higher (GG2+) disease, as some men may have volume measurements available at the ...time of blood draw. While prostate volume predicts biopsy outcome, it requires an imaging procedure for measurement. The four kallikrein panel - commercially available as the 4Kscore - predicts risk of GG2+ disease and requires only a blood draw.
A total of 9131 patients with available prostate volume and total PSA ≤25 ng/ml from 5 historical (sextant biopsy, pre-ISUP 2005 grading) and 4 contemporary cohorts (10+ cores, ISUP 2005 grading). Previously published kallikrein panel models were used to predict risk of GG2+. Volume was added to the model in each cohort and change in discrimination was meta-analyzed.
Increased prostate volume was associated with decreased risk of GG2+ disease after controlling for the kallikrein panel in 7/9 cohorts. However, kallikrein panel discrimination (0.817, 95% CI 0.802, 0.831) was not improved after including volume (AUC difference 0.002, 95% CI -0.003, 0.006). Heterogeneity (P <.0001) was driven by an AUC increase in 1 cohort of academic cancer centers (0.044, 95% CI 0.025, 0.064), with no evidence of heterogeneity after excluding this cohort (P = .15).
The kallikrein panel provides a non-invasive approach to assess the risk of high-grade prostate cancer. Our results do not justify the inclusion of prostate volume in the four kallikrein panel. There is some evidence that the predictive value of prostate volume is provider dependent: further research is needed to address this question.
Prostate cancer prediction tools provide quantitative guidance for doctor-patient decision-making regarding biopsy. The widely used online Prostate Cancer Prevention Trial Risk Calculator (PCPTRC) ...utilized data from the 1990s based on six-core biopsies and outdated grading systems.
We prospectively gathered data from men undergoing prostate biopsy in multiple diverse North American and European institutions participating in the Prostate Biopsy Collaborative Group (PBCG) in order to build a state-of-the-art risk prediction tool.
We obtained data from 15 611 men undergoing 16 369 prostate biopsies during 2006–2017 at eight North American institutions for model-building and three European institutions for validation.
We used multinomial logistic regression to estimate the risks of high-grade prostate cancer (Gleason score ≥7) on biopsy based on clinical characteristics, including age, prostate-specific antigen, digital rectal exam, African ancestry, first-degree family history, and prior negative biopsy. We compared the PBCG model to the PCPTRC using internal cross-validation and external validation on the European cohorts.
Cross-validation on the North American cohorts (5992 biopsies) yielded the PBCG model area under the receiver operating characteristic curve (AUC) as 75.5% (95% confidence interval: 74.2–76.8), a small improvement over the AUC of 72.3% (70.9–73.7) for the PCPTRC (p<0.0001). However, calibration and clinical net benefit were far superior for the PBCG model. Using a risk threshold of 10%, clinical use of the PBCG model would lead to the equivalent of 25 fewer biopsies per 1000 patients without missing any high-grade cancers. Results were similar on external validation on 10 377 European biopsies.
The PBCG model should be used in place of the PCPTRC for prediction of prostate biopsy outcome.
A contemporary risk tool for outcomes on prostate biopsy based on the routine clinical risk factors is now available for informed decision-making.
A North American multicohort-based risk tool for predicting prostate cancer outcomes on biopsy has been developed and outperformed a leading North American risk tool in validation. It is now available online for patients and their providers.
We compared six commonly used logistic regression methods for accommodating missing risk factor data from multiple heterogeneous cohorts, in which some cohorts do not collect some risk factors at ...all, and developed an online risk prediction tool that accommodates missing risk factors from the end-user.
Ten North American and European cohorts from the Prostate Biopsy Collaborative Group (PBCG) were used for fitting a risk prediction tool for clinically significant prostate cancer, defined as Gleason grade group ≥ 2 on standard TRUS prostate biopsy. One large European PBCG cohort was withheld for external validation, where calibration-in-the-large (CIL), calibration curves, and area-underneath-the-receiver-operating characteristic curve (AUC) were evaluated. Ten-fold leave-one-cohort-internal validation further validated the optimal missing data approach.
Among 12,703 biopsies from 10 training cohorts, 3,597 (28%) had clinically significant prostate cancer, compared to 1,757 of 5,540 (32%) in the external validation cohort. In external validation, the available cases method that pooled individual patient data containing all risk factors input by an end-user had best CIL, under-predicting risks as percentages by 2.9% on average, and obtained an AUC of 75.7%. Imputation had the worst CIL (-13.3%). The available cases method was further validated as optimal in internal cross-validation and thus used for development of an online risk tool. For end-users of the risk tool, two risk factors were mandatory: serum prostate-specific antigen (PSA) and age, and ten were optional: digital rectal exam, prostate volume, prior negative biopsy, 5-alpha-reductase-inhibitor use, prior PSA screen, African ancestry, Hispanic ethnicity, first-degree prostate-, breast-, and second-degree prostate-cancer family history.
Developers of clinical risk prediction tools should optimize use of available data and sources even in the presence of high amounts of missing data and offer options for users with missing risk factors.
Visual abstracts increase the social media reach of new urology literature compared to manuscript key figures, but were associated with a significantly lower article click-through rate. In the ...increasingly virtual world of academic medicine, these findings may assist authors, editors, and publishers with new research dissemination.
Visual abstracts (VAs) are graphical representations of the key findings in manuscripts and have been adopted by many journals to improve content dissemination via social media. We sought to assess whether VAs, compared to key figures (KFs), increased reader engagement via social media using articles published in European Urology. We prospectively randomized 200 consecutive new publications to representation on Twitter and Instagram using either a VA (n = 99) or a KF (n = 101). Randomization was stratified by prostate cancer content. The primary outcome was Twitter impressions. Secondary outcomes included Twitter total engagements, link clicks, likes, and retweets, as well as Instagram likes. Analysis of covariance was conducted using the stratification variable as a covariate. We found that Twitter impressions were greater for tweets containing VAs compared to KFs (8385 vs 6882; adjusted difference 1480, 95% confidence interval CI 434–2526; p = 0.006). VA use was also associated with more retweets and likes (p < 0.002), but fewer full-article link clicks than KFs (60 vs 105, adjusted difference 45, 95% CI 21–70; p = 0.0004). The choice between VA and KF should depend on the relative value given to impressions versus full-article link clicks.
We found that use of a visual abstract increases the social media reach of new urology articles when compared to key figures from the manuscript, but was associated in a significantly lower click-through rate. In the increasingly virtual world of academic medicine, these findings may assist authors, editors, and publishers with dissemination of new research.
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