806 research outputs found
The evidence base of US Food and Drug Administration approvals of novel cancer therapies from 2000 to 2020
Concerns have been raised that regulatory programs to accelerate approval of cancer drugs in cancer may increase uncertainty about benefits and harms for survival and quality of life (QoL). We analyzed all pivotal clinical trials and all non-pivotal randomized controlled trials (RCTs) for all cancer drugs approved for the first time by the FDA between 2000 and 2020. We report regulatory and trial characteristics. Effects on overall survival (OS), progression-free survival and tumor response were summarized in meta-analyses. Effects on QoL were qualitatively summarized. Between 2000 and 2020, the FDA approved 145 novel cancer drugs for 156 indications based on 190 clinical trials. Half of indications (49%) were approved without RCT evidence; 82% had a single clinical trial only. OS was primary endpoint in 14% of trials and QoL data were available from 25%. The median OS benefit was 2.55 months (IQR, 1.33-4.28) with a mean hazard ratio for OS of 0.75 (95%CI, 0.72-0.79, I2 = 42). Improvement for QoL was reported for 7 (4%) of 156 indications. Over time, priority review was used increasingly and the mean number of trials per indication decreased from 1.45 to 1.12. More trials reported results on QoL (19% in 2000-2005; 41% in 2016-2020). For 21 years, novel cancer drugs have typically been approved based on one single, often uncontrolled, clinical trial, measuring surrogate endpoints. This leaves cancer patients without solid evidence that novel drugs improve their survival or QoL and there is no indication towards improvement
Advances in cyclin-dependent kinase inhibitors for the treatment of melanoma
Despite the recent advances in the treatment of malignant melanoma with immunotherapy and BRAF/MEK targeted agents, advanced disease still beholds a poor prognosis for a significant proportion of patients. Cyclin dependent kinase (CDK) inhibitors have been investigated as novel melanoma therapeutics throughout a range of phase 1 and 2 trials, as single agents and in combination with established treatments. Areas covered: This article summarises the rationale for, and development of CDK inhibitors in melanoma, with their evolution from pan-CDK inhibitors to highly specific agents, throughout clinical trials and finally their potential future use. Expert opinion: Whilst CDK inhibitors have been practice changing in breast cancer management, their efficacy is yet to be proven in melanoma. Combination with BRAF/MEK inhibitors has been hindered by dose limiting toxicities, but their role may yet to be found within the spectrum of biomarker derived personalised melanoma management. The effect that CDK inhibitors can have as an adjunct to immunotherapy also remains to be seen
Social prescribing in Greater Manchester
This report presents key findings from a mapping
and research exercise undertaken by the University of
Salford and Salford CVS from February to May of 2018.
The research was designed to fill an important gap in our
knowledge about what social prescribing activities already
exist in Greater Manchester (GM), whether there exists
any kind of emerging consensus around models or best
practices within this GM context, and how this relates to
best practices existing across the UK
Flow-Based Single Cell Deposition for High-Throughput Screening of Protein Libraries
The identification and engineering of proteins having refined or novel characteristics is an important area of research in many scientific fields. Protein modelling has enabled the rational design of unique proteins, but high-throughput screening of large libraries is still required to identify proteins with potentially valuable properties. Here we report on the development and evaluation of a novel fluorescent activated cell sorting based screening platform. Single bacterial cells, expressing a protein library to be screened, are electronically sorted and deposited onto plates containing solid nutrient growth media in a dense matrix format of between 44 and 195 colonies/cm2. We show that this matrix format is readily applicable to machine interrogation (<30 seconds per plate) and subsequent bioinformatic analysis (~60 seconds per plate) thus enabling the high-throughput screening of the protein library. We evaluate this platform and show that bacteria containing a bioluminescent protein can be spectrally analysed using an optical imager, and a rare clone (0.5% population) can successfully be identified, picked and further characterised. To further enhance this screening platform, we have developed a prototype electronic sort stream multiplexer, that when integrated into a commercial flow cytometric sorter, increases the rate of colony deposition by 89.2% to 24 colonies per second. We believe that the screening platform described here is potentially the foundation of a new generation of high-throughput screening technologies for proteins
Ancient Egypt 1915 Part 4
Part 4 of the 1915 Ancient Egypt books. Contents include discoveries at Lisht, a third century statuette, archaic burials in Libya, and the university college museum.https://knowledge.e.southern.edu/kweeks_coll/1004/thumbnail.jp
Oncologist-led BRCA ‘mainstreaming’ in the ovarian cancer clinic: A study of 255 patients and its impact on their management
Although guidelines recommend BRCA testing for all women with non-mucinous epithelial ovarian cancer, there is significant variability in access to testing across the UK. A germline BRCA mutation (BRCAm) in ovarian cancer patients provides prognostic and predictive information and influences clinical management, such as the use of PARP inhibitors, which have demonstrated a progression-free survival benefit in the BRCAm cohort. Additionally, the finding of a BRCAm has significant implications for patients and their families in terms of cancer risk and prevention. We studied the impact of a newly-formed, oncologist-led ‘mainstreaming’ germline BRCA testing pathway in 255 ovarian cancer patients at Imperial College NHS Trust. Prior to the establishment of ‘mainstreaming’, uptake of germline BRCA testing was 14% with a mean turnaround time of 148.2 calendar days. The ‘mainstreaming’ approach led to a 95% uptake of germline BRCA testing and a mean turnaround time of 20.6 days. Thirty-four (13.33%) BRCAm patients were identified. At the time of data collection nine BRCAm patients had received a PARP inhibitor off-trial, three had entered a PARP inhibitor trial and 5 were receiving platinum-based chemotherapy with a plan to receive PARP inhibitor maintenance. This study provides further evidence of the impact of oncologist-led ‘mainstreaming’ programs
Improved hepatic arterial fraction estimation using cardiac output correction of arterial input functions for liver DCE MRI
Liver dynamic contrast enhanced (DCE) MRI pharmacokinetic modelling could be useful in the assessment of diffuse liver disease and focal liver lesions, but is compromised by errors in arterial input function (AIF) sampling. In this study, we apply cardiac output correction to arterial input functions (AIFs) for liver dynamic contrast enhanced (DCE) MRI and investigate the effect on dual-input single compartment hepatic perfusion parameter estimation and reproducibility. Thirteen healthy volunteers (28.7±1.94 years, seven males) underwent liver DCE MRI and cardiac output measurement using aortic root phase contrast MRI (PCMRI), with reproducibility (n=9) measured at seven days. Cardiac output AIF correction was undertaken by constraining the first pass AIF enhancement curve using the indicator-dilution principle. Hepatic perfusion parameters with and without cardiac output AIF correction were compared and seven-day reproducibility assessed. Differences between cardiac output corrected and uncorrected liver DCE MRI portal venous (PV) perfusion (p=0.066), total liver blood flow (TLBF)(p=0.101), hepatic arterial (HA) fraction (p=0.895), mean transit time (MTT)(p=0.646), distribution volume (DV)(p=0.890) were not significantly different. Seven-day corrected HA fraction reproducibility was improved (mean difference 0.3%, Bland-Altman 95% Limits-of-Agreement (BA95%LoA) ±27.9%, Coefficient of Variation (CoV) 61.4% vs 9.3%, ±35.5%, 81.7% respectively without correction). Seven-day uncorrected PV perfusion was also improved (mean difference 9.3 ml/min/100g, BA95%LoA ±506.1 ml/min/100g, CoV 64.1% vs 0.9 ml/min/100g, ±562.8 ml/min/100g, 65.1% respectively with correction) as was uncorrected TLBF(mean difference 43.8 ml/min/100g, BA95%LoA ±586.7 ml/min/100g, CoV 58.3% vs 13.3 ml/min/100g, ±661.5 ml/min/100g, 60.9% respectively with correction). Reproducibility of uncorrected MTT was similar (uncorrected mean difference 2.4s, BA95%LoA ±26.7s, CoV 60.8% uncorrected vs 3.7s, ±27.8s, 62.0% respectively with correction), as was and DV (uncorrected mean difference 14.1%, BA95%LoA ±48.2%, CoV 24.7% vs 10.3%, ±46.0%, 23.9% respectively with correction). Cardiac output AIF correction does not significantly affect the estimation of hepatic perfusion parameters but demonstrates improvements in normal volunteer seven-day HA fraction reproducibility, but deterioration in PV perfusion and TLBF reproducibility. Improved HA fraction reproducibility maybe important as arterialisation of liver perfusion is increased in chronic liver disease and within malignant liver lesions
Neoadjuvant chemotherapy and trastuzumab versus neoadjuvant chemotherapy followed by post-operative trastuzumab for patients with HER2-positive breast cancer
Neoadjuvant chemotherapy plus trastuzumab (NCT) increases the rate of pathological complete response (pCR) and event-free survival (EFS) compared to neoadjuvant chemotherapy (NC) alone in women with HER2 positive breast cancer (BC). pCR in this setting is associated with improved EFS. Whether NCT preferentially improves EFS in comparison to NC followed by adjuvant trastuzumab initiated postoperatively (NCAT) has not been addressed. Using clinical data from women with HER2 positive BC treated at 7 European institutions between 2007 and 2010 we sought to investigate the impact on breast cancer outcomes of concomitant (NCT) versus sequential (NCAT) treatment in HER2 positive early BC. The unadjusted hazard ratio (HR) for event free survival with NCT compared with NCAT was 0.63 (95% CI 0.37–1.08; p = 0.091). Multivariable analysis revealed that treatment group, tumour size and ER status were significantly associated with EFS from diagnosis. In the whole group NCT was associated with a reduced risk of an event relative to NCAT, an effect that was confined to ER negative (HR: 0.25; 95% CI, 0.10–0.62; p = 0.003) as opposed to ER positive tumours (HR: 1.07; 95% CI, 0.46–2.52; p = 0.869). HER2 positive/ER negative BC treated with NC gain greatest survival benefit when trastuzumab is administered in both the neoadjuvant and adjuvant period rather than in the adjuvant period alone. These data support the early introduction of targeted combination therapy in HER2 positive/ER negative BC
Latent class modelling with a time-to-event distal outcome: A comparison of one, two and three-step approaches
Latent class methods can be used to identify unobserved subgroups which differ in their observed data. Researchers are often interested in outcomes for the identified subgroups and in some disciplines time-to-event outcome measures are common, e.g., overall survival in oncology. In this study Monte Carlo simulation is used to evaluate the empirical properties of latent class effect estimates on a time-to-event distal outcome using one, two and three-step approaches. Both standard and inclusive bias-corrected three-step approaches are considered. One-step latent class effect estimates are shown to be superior to the evaluated alternatives. Both the two-step approach and a standard three-step approach, where subjects are partially assigned to latent classes, produced unbiased estimates with nominal confidence interval coverage when latent classes were well separated, but not otherwise. Keywords: latent class analysis, time-to-event, two-step, joint modeling</p
Radio-metal cross-linking of alginate hydrogels for non-invasive in vivo imaging
Alginate hydrogels are cross-linked polymers with high water content, tuneable chemical and material properties, and a range of biomedical applications including drug delivery, tissue engineering, and cell therapy. However, their similarity to soft tissue often renders them undetectable within the body using conventional bio-medical imaging techniques. This leaves much unknown about their behaviour in vivo, posing a challenge to therapy development and validation. To address this, we report a novel, fast, and simple method of incorporating the nuclear imaging radio-metal 111In into the structure of alginate hydrogels by utilising its previously-undescribed capacity as an ionic cross-linking agent. This enabled non-invasive in vivo nuclear imaging of hydrogel delivery and retention across the whole body, over time, and across a range of model therapies including: nasal and oral drug delivery, stem cell transplantation, and cardiac tissue engineering. This information will facilitate the development of novel therapeutic hydrogel formulations, encompassing alginate, across disease categories
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