Publications by authors named "David J Harrison"

212 Publications

RAMPART: A model for a regulatory-ready academic-led phase III trial in the adjuvant renal cell carcinoma setting.

Contemp Clin Trials 2021 Sep 16;108:106481. Epub 2021 Sep 16.

MRC Clinical Trials Unit at UCL, Institute of Clinical Trials & Methodology, 2nd Floor 90 High Holborn, London WC1V 6LJ.

The development of therapeutics in oncology is a highly active research area for the pharmaceutical and biotechnology industries, but also has a strong academic base. Many new agents have been developed in recent years, most with specific biological targets. This has mandated the need to look at different ways to streamline the evaluation of new agents. One solution has been the development of adaptive trial designs that allow the evaluation of multiple agents, concentrating on the most promising agents while screening out those which are unlikely to benefit patients. Another way forward has been the growth of partnerships between academia and industry with the shared goal of designing and conducting high quality clinical trials which answer important clinical questions as efficiently as possible. The RAMPART trial (NCT03288532) brings together both of these processes in an attempt to improve outcomes for patients with locally advanced renal cell carcinoma (RCC), where no globally acceptable adjuvant strategy after nephrectomy currently exist. RAMPART is led by the MRC CTU at University College London (UCL), in collaboration with other international academic groups and industry. We aim to facilitate the use of data from RAMPART, (dependent on outcomes), for a future regulatory submission that will extend the license of the agents being investigated. We share our experience in order to lay the foundations for an effective trial design and conduct framework and to guide others who may be considering similar collaborations. Trial Registration: ISRCTN #: ISRCTN53348826, NCT #: NCT03288532, EUDRACT #: 2017-002329-39. CTA #: 20363/0380/001-0001. MREC #: 17/LO/1875. ClinicalTrials.gov Identifier: NCT03288532 RAMPART grant number: MC_UU_12023/25. . RAMPART Protocol version 5.0.
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http://dx.doi.org/10.1016/j.cct.2021.106481DOI Listing
September 2021

The novel nucleoside analogue ProTide NUC-7738 overcomes cancer resistance mechanisms in vitro and in a first-in-human Phase 1 clinical trial.

Clin Cancer Res 2021 Sep 8. Epub 2021 Sep 8.

Oncology, University of Oxford

Purpose: Nucleoside analogues form the backbone of many therapeutic regimens in oncology and require the presence of intracellular enzymes for their activation. A ProTide is comprised of a nucleoside fused to a protective phosphoramidate cap. ProTides are easily incorporated into cells whereupon the cap is cleaved and a pre-activated nucleoside released. 3'-deoxyadenosine (3'-dA) is a naturally-occurring adenosine analogue with established anti-cancer activity in vitro but limited bioavailability due to its rapid in vivo deamination by the circulating enzyme adenosine deaminase, poor uptake into cells and reliance on adenosine kinase for its activation. In order to overcome these limitations, 3'-dA was chemically modified to create the novel ProTide NUC-7738.

Experimental Design: We describe the synthesis of NUC-7738. We determine the IC of NUC-7738 using pharmacokinetics (PK) and conduct genome-wide analyses to identify its mechanism of action using different cancer model systems. We validate these findings in cancer patients.

Results: We show that NUC-7738 overcomes the cancer resistance mechanisms that limit the activity of 3'-dA and that its activation is dependent on ProTide cleavage by the enzyme histidine triad nucleotide binding protein 1. PK and tumour samples obtained from the ongoing first-in-human Phase 1 clinical trial of NUC-7738 further validate our findings and show NUC-7738 is an effective pro-apoptotic agent in cancer cells with effects on the NF-kappaB pathway.

Conclusions: Our study provides proof that NUC-7738 overcomes cellular resistance mechanisms and support its further clinical evaluation as a novel cancer treatment within the growing pantheon of anti-cancer ProTides.
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http://dx.doi.org/10.1158/1078-0432.CCR-21-1652DOI Listing
September 2021

The modification of cancer risk by chemicals.

Toxicol Res (Camb) 2021 Aug 12;10(4):800-809. Epub 2021 Jul 12.

School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Byrom Street, Liverpool L3 3AF, UK.

Advances in understanding of the process of carcinogenesis have undermined the concept of chemicals being classifiable as either carcinogens or non-carcinogens. Elements of carcinogenesis are happening all the time and a proportion of cancers cannot be prevented, the 'bad luck hypothesis'. Although the proportion that can be prevented is disputed, it is important to continue efforts to reduce it. Factors that increase cancer risk have been grouped into intrinsic factors that cannot be modified, and endogenous and exogenous factors that can be modified. Chemicals are exogenous factors that can be modified by risk management measures. Chemicals can alter three key rates that influence cancer risk: cell division, mutation rate per cell division, transformation rate of mutated cells to cancer. These rates can form the basis of a dynamic cancer risk model, a generic, adverse outcome pathway for carcinogenesis where chemicals are considered for their ability to modify cancer risk rather than simply whether they are classed as carcinogens or non-carcinogens. This allows the development of different strategies for assessing cancer risk that use a range of data sources and are not dependent on using long-term bioassays and epidemiology to identify carcinogens. The framework will also allow difficult questions such as the effect of less than lifetime exposures and the effect of exposures to more than one chemical to be addressed.
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http://dx.doi.org/10.1093/toxres/tfab064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8403608PMC
August 2021

YAP Translocation Precedes Cytoskeletal Rearrangement in Podocyte Stress Response: A Podometric Investigation of Diabetic Nephropathy.

Front Physiol 2021 15;12:625762. Epub 2021 Jul 15.

School of Medicine, University of St Andrews, St Andrews, United Kingdom.

Podocyte loss plays a pivotal role in the pathogenesis of glomerular disease. However, the mechanisms underlying podocyte damage and loss remain poorly understood. Although detachment of viable cells has been documented in experimental Diabetic Nephropathy, correlations between reduced podocyte density and disease severity have not yet been established. YAP, a mechanosensing protein, has recently been shown to correlate with glomerular disease progression, however, the underlying mechanism has yet to be fully elucidated. In this study, we sought to document podocyte density in Diabetic Nephropathy using an amended podometric methodology, and to investigate the interplay between YAP and cytoskeletal integrity during podocyte injury. Podocyte density was quantified using TLE4 and GLEPP1 multiplexed immunofluorescence. Fourteen Diabetic Nephropathy cases were analyzed for both podocyte density and cytoplasmic translocation of YAP via automated image analysis. We demonstrate a significant decrease in podocyte density in Grade III/IV cases (124.5 per 10 μm) relative to Grade I/II cases (226 per 10 μm) (Student's -test, < 0.001), and further show that YAP translocation precedes cytoskeletal rearrangement following injury. Based on these findings we hypothesize that a significant decrease in podocyte density in late grade Diabetic Nephropathy may be explained by early cytoplasmic translocation of YAP.
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http://dx.doi.org/10.3389/fphys.2021.625762DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8320019PMC
July 2021

Placental endocrine insufficiency programs anxiety, deficits in cognition and atypical social behaviour in offspring.

Hum Mol Genet 2021 Sep;30(19):1863-1880

Biomedicine Division, School of Biosciences, Cardiff University, Cardif CF10 3AX, UK.

Abnormally elevated expression of the imprinted PHLDA2 gene has been reported in the placenta of human babies that are growth restricted in utero in several studies. We previously modelled this gene alteration in mice and found that just 2-fold increased expression of Phlda2 resulted in placental endocrine insufficiency. In addition, elevated Phlda2 was found to drive fetal growth restriction (FGR) of transgenic offspring and impaired maternal care by their wildtype mothers. Being born small and being exposed to suboptimal maternal care have both been associated with the increased risk of mental health disorders in human populations. In the current study we probed behavioural consequences of elevated Phlda2 for the offspring. We discovered increased anxiety-like behaviours, deficits in cognition and atypical social behaviours, with the greatest impact on male offspring. Subsequent analysis revealed alterations in the transcriptome of the adult offspring hippocampus, hypothalamus and amygdala, regions consistent with these behavioural observations. The inclusion of a group of fully wildtype controls raised in a normal maternal environment allowed us to attribute behavioural and molecular alterations to the adverse maternal environment induced by placental endocrine insufficiency rather than the specific gene change of elevated Phlda2. Our work demonstrates that a highly common alteration reported in human FGR is associated with negative behavioural outcomes later in life. Importantly, we also establish the experimental paradigm that placental endocrine insufficiency can program atypical behaviour in offspring highlighting the under-appreciated role of placental endocrine insufficiency in driving disorders of later life behaviour.
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http://dx.doi.org/10.1093/hmg/ddab154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8444454PMC
September 2021

Assessment of Immunological Features in Muscle-Invasive Bladder Cancer Prognosis Using Ensemble Learning.

Cancers (Basel) 2021 Apr 1;13(7). Epub 2021 Apr 1.

School of Medicine, University of St Andrews, St Andrews KY16 9TF, UK.

The clinical staging and prognosis of muscle-invasive bladder cancer (MIBC) routinely includes the assessment of patient tissue samples by a pathologist. Recent studies corroborate the importance of image analysis in identifying and quantifying immunological markers from tissue samples that can provide further insight into patient prognosis. In this paper, we apply multiplex immunofluorescence to MIBC tissue sections to capture whole-slide images and quantify potential prognostic markers related to lymphocytes, macrophages, tumour buds, and PD-L1. We propose a machine-learning-based approach for the prediction of 5 year prognosis with different combinations of image, clinical, and spatial features. An ensemble model comprising several functionally different models successfully stratifies MIBC patients into two risk groups with high statistical significance ( value < 1×10-5). Critical to improving MIBC survival rates, our method correctly classifies 71.4% of the patients who succumb to MIBC, which is significantly more than the 28.6% of the current clinical gold standard, the TNM staging system.
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http://dx.doi.org/10.3390/cancers13071624DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8036815PMC
April 2021

Automated Detection and Classification of Desmoplastic Reaction at the Colorectal Tumour Front Using Deep Learning.

Cancers (Basel) 2021 Mar 31;13(7). Epub 2021 Mar 31.

Quantitative and Digital Pathology, School of Medicine, University of St Andrews, St Andrews KY16 9TF, UK.

The categorisation of desmoplastic reaction (DR) present at the colorectal cancer (CRC) invasive front into mature, intermediate or immature type has been previously shown to have high prognostic significance. However, the lack of an objective and reproducible assessment methodology for the assessment of DR has been a major hurdle to its clinical translation. In this study, a deep learning algorithm was trained to automatically classify immature DR on haematoxylin and eosin digitised slides of stage II and III CRC cases ( = 41). When assessing the classifier's performance on a test set of patient samples ( = 40), a Dice score of 0.87 for the segmentation of myxoid stroma was reported. The classifier was then applied to the full cohort of 528 stage II and III CRC cases, which was then divided into a training ( = 396) and a test set ( = 132). Automatically classed DR was shown to have superior prognostic significance over the manually classed DR in both the training and test cohorts. The findings demonstrated that deep learning algorithms could be applied to assist pathologists in the detection and classification of DR in CRC in an objective, standardised and reproducible manner.
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http://dx.doi.org/10.3390/cancers13071615DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8036363PMC
March 2021

A Phase Ib Open-Label, Dose-Escalation Study of NUC-1031 in Combination with Carboplatin for Recurrent Ovarian Cancer.

Clin Cancer Res 2021 Jun 19;27(11):3028-3038. Epub 2021 Mar 19.

Early Phase Clinical Trials Unit, Department of Oncology, University of Oxford, Oxford, United Kingdom.

Purpose: NUC-1031 is a first-in-class ProTide modification of gemcitabine. In PRO-002, NUC-1031 was combined with carboplatin in recurrent ovarian cancer.

Patients And Methods: NUC-1031 was administered on days 1 and 8 with carboplatin on day 1 every 3 weeks for up to six cycles. Four dose cohorts of NUC-1031 (500, 625, and 750 mg/m) with carboplatin (AUC4 or 5) were investigated. Primary endpoint was recommended phase II combination dose (RP2CD). Secondary endpoints included safety, investigator-assessed objective response rate (ORR), clinical benefit rate (CBR), progression-free survival (PFS), and pharmacokinetics.

Results: A total of 25 women with recurrent ovarian cancer, a mean of 3.8 prior lines of chemotherapy, and a median platinum-free interval of 5 months (range: 7-451 days) were enrolled; 15 of 25 (60%) were platinum resistant, 9 (36%) were partially platinum sensitive, and 1 (4%) was platinum sensitive. Of the 23 who were response evaluable, there was 1 confirmed complete response (4%), 5 partial responses (17%), and 8 (35%) stable disease. The ORR was 26% and CBR was 74% across all doses and 100% in the RP2CD cohort. Median PFS was 27.1 weeks. NUC-1031 was stable in the plasma and rapidly generated high intracellular dFdCTP levels that were unaffected by carboplatin.

Conclusions: NUC-1031 combined with carboplatin is well tolerated in recurrent ovarian cancer. Highest efficacy was observed at the RP2CD of 500 mg/m NUC-1031 on days 1 and 8 with AUC5 carboplatin day 1, every 3 weeks for six cycles. The ability to deliver carboplatin at AUC5 and the efficacy of this schedule even in patients with platinum-resistant disease makes this an attractive therapeutic combination.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-4403DOI Listing
June 2021

Healthcare resource utilization and associated cost of patients with bone metastases from solid tumors who are naïve to bone-targeting agents: a comparative analysis of patients with and without skeletal-related events.

Eur J Health Econ 2021 Mar 18;22(2):243-254. Epub 2021 Jan 18.

Centrum for Hematology and Oncology, Im Prüfling 17-19, 60389, Frankfurt a. Main, Germany.

Background: This study analyzes the impact of skeletal-related events (SRE) on healthcare resource utilization (HCRU) and costs incurred by patients with bone metastases (BM) from solid tumors (ST), who are therapy-naïve to bone targeting agents (BTAs).

Methods: German claims data from 01/01/2010 to 30/06/2018 were used to conduct a retrospective comparative cohort analysis of BTA-naive patients with a BM diagnosis and preceding ST diagnosis. HCRU and treatment-related costs were compared in two matched cohorts of patients with and without a history of SREs, defined as pathological fracture, spinal cord compression, surgery to bone and radiation to bone. The first SRE was defined as the patient-individual index date. Conversely, for the non-SRE patients, index dates were assigned randomly.

Results: In total, 45.20% of 9,832 patients reported experiencing at least one SRE (n = 4444) while 54.80% experienced none (n = 5388); 2,434 pairs of SRE and non-SRE patients were finally matched (mean age: 70.87/71.07 years; females: 39.07%/38.58%). Between SRE and non-SRE cohorts, significant differences in the average number of hospitalization days per patient-year (35.80/30.80) and associated inpatient-care costs (14,199.27€/10,787.31€) were observed. The total cost ratio was 1.16 (p < 0.001) with an average cost breakdown of 23,689.54€ and 20,403.27€ per patient-year in SRE and non-SRE patients.

Conclusion: The underutilization of BTAs within a clinical setting poses an ongoing challenge in the real-world treatment of BM patients throughout Germany. Ultimately, the economic burden of treating SREs in patients with BM from ST was found to be considerable, resulting in higher direct healthcare costs and increased utilization of inpatient care facilities.
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http://dx.doi.org/10.1007/s10198-020-01247-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7881971PMC
March 2021

Computerized Image Analysis of Tumor Cell Nuclear Morphology Can Improve Patient Selection for Clinical Trials in Localized Clear Cell Renal Cell Carcinoma.

J Pathol Inform 2020 6;11:35. Epub 2020 Nov 6.

School of Medicine, University of St Andrews and Lothian NHS University Hospitals, St Andrews, Scotland.

Background: Clinicopathological scores are used to predict the likelihood of recurrence-free survival for patients with clear cell renal cell carcinoma (ccRCC) after surgery. These are fallible, particularly in the middle range. This inevitably means that a significant proportion of ccRCC patients who will not develop recurrent disease enroll into clinical trials. As an exemplar of using digital pathology, we sought to improve the predictive power of "recurrence free" designation in localized ccRCC patients, by precise measurement of ccRCC nuclear morphological features using computational image analysis, thereby replacing manual nuclear grade assessment.

Materials And Methods: TNM 8 UICC pathological stage pT1-pT3 ccRCC cases were recruited in Scotland and in Singapore. A Leibovich score (LS) was calculated. Definiens Tissue studio® (Definiens GmbH, Munich) image analysis platform was used to measure tumor nuclear morphological features in digitized hematoxylin and eosin (H&E) images.

Results: Replacing human-defined nuclear grade with computer-defined mean perimeter generated a modified Leibovich algorithm, improved overall specificity 0.86 from 0.76 in the training cohort. The greatest increase in specificity was seen in LS 5 and 6, which went from 0 to 0.57 and 0.40, respectively. The modified Leibovich algorithm increased the specificity from 0.84 to 0.94 in the validation cohort.

Conclusions: CcRCC nuclear mean perimeter, measured by computational image analysis, together with tumor stage and size, node status and necrosis improved the accuracy of predicting recurrence-free in the localized ccRCC patients. This finding was validated in an ethnically different Singaporean cohort, despite the different H and E staining protocol and scanner used. This may be a useful patient selection tool for recruitment to multicenter studies, preventing some patients from receiving unnecessary additional treatment while reducing the number of patients required to achieve adequate power within neoadjuvant and adjuvant clinical studies.
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http://dx.doi.org/10.4103/jpi.jpi_13_20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7737492PMC
November 2020

Tissue-Specific Immunopathology in Fatal COVID-19.

Am J Respir Crit Care Med 2021 01;203(2):192-201

Centre for Inflammation Research, Queen's Medical Research Institute, and.

In life-threatening coronavirus disease (COVID-19), corticosteroids reduce mortality, suggesting that immune responses have a causal role in death. Whether this deleterious inflammation is primarily a direct reaction to the presence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or an independent immunopathologic process is unknown. To determine SARS-CoV-2 organotropism and organ-specific inflammatory responses and the relationships among viral presence, inflammation, and organ injury. Tissue was acquired from 11 detailed postmortem examinations. SARS-CoV-2 organotropism was mapped by using multiplex PCR and sequencing, with cellular resolution achieved by viral S (spike) protein detection. Histologic evidence of inflammation was quantified from 37 anatomic sites, and the pulmonary immune response was characterized by using multiplex immunofluorescence. Multiple aberrant immune responses in fatal COVID-19 were found, principally involving the lung and reticuloendothelial system, and these were not clearly topologically associated with the virus. Inflammation and organ dysfunction did not map to the tissue and cellular distribution of SARS-CoV-2 RNA and protein between or within tissues. An arteritis was identified in the lung, which was further characterized as a monocyte/myeloid-rich vasculitis, and occurred together with an influx of macrophage/monocyte-lineage cells into the pulmonary parenchyma. In addition, stereotyped abnormal reticuloendothelial responses, including excessive reactive plasmacytosis and iron-laden macrophages, were present and dissociated from viral presence in lymphoid tissues. Tissue-specific immunopathology occurs in COVID-19, implicating a significant component of the immune-mediated, virus-independent immunopathologic process as a primary mechanism in severe disease. Our data highlight novel immunopathologic mechanisms and validate ongoing and future efforts to therapeutically target aberrant macrophage and plasma-cell responses as well as promote pathogen tolerance in COVID-19.
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http://dx.doi.org/10.1164/rccm.202008-3265OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7874430PMC
January 2021

Spatial immune profiling of the colorectal tumor microenvironment predicts good outcome in stage II patients.

NPJ Digit Med 2020 15;3:71. Epub 2020 May 15.

1Quantitative and Digital Pathology, School of Medicine, University of St Andrews, St Andrews, KY16 9TF UK.

Cellular subpopulations within the colorectal tumor microenvironment (TME) include CD3 and CD8 lymphocytes, CD68 and CD163 macrophages, and tumor buds (TBs), all of which have known prognostic significance in stage II colorectal cancer. However, the prognostic relevance of their spatial interactions remains unknown. Here, by applying automated image analysis and machine learning approaches, we evaluate the prognostic significance of these cellular subpopulations and their spatial interactions. Resultant data, from a training cohort retrospectively collated from Edinburgh, UK hospitals ( = 113), were used to create a combinatorial prognostic model, which identified a subpopulation of patients who exhibit 100% survival over a 5-year follow-up period. The combinatorial model integrated lymphocytic infiltration, the number of lymphocytes within 50-μm proximity to TBs, and the CD68/CD163 macrophage ratio. This finding was confirmed on an independent validation cohort, which included patients treated in Japan and Scotland ( = 117). This work shows that by analyzing multiple cellular subpopulations from the complex TME, it is possible to identify patients for whom surgical resection alone may be curative.
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http://dx.doi.org/10.1038/s41746-020-0275-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7229187PMC
May 2020

Unified Behavioral Scoring for Preclinical Models.

Front Neurosci 2020 7;14:313. Epub 2020 Apr 7.

Preg Lab, School of Biosciences, Cardiff University, Cardiff, United Kingdom.

Preclinical mental health research relies upon animal models, and whilst many encouraging advances are being made, reproducibility and translational relevance may be limited by sub-optimal testing or model choices. Animal behaviors are complex and test batteries should be designed to include their multifaceted nature. However, multiple behavioral testing is often avoided due to cost, availability or statistical rigor. Additionally, despite the disparity in the incidence of mental health problems between the sexes, a move toward reducing animal numbers could be a deterrent to including both male and female animals. The current study introduces a unified scoring system for specific behavioral traits with the aim of maximizing the use of all data generated whilst reducing the incidence of statistical errors. Female and male mice from two common background strains were tested on behavior batteries designed to probe multiple aspects of anxiety-related and social behavioral traits. Results for every outcome measure were normalized to generate scores for each test and combined to give each mouse a single unified score for each behavioral trait. The unified behavioral scores revealed clear differences in the anxiety and stress-related, and sociability traits of mice. Principle component analysis of data demonstrated significant clustering of animals into their experimental groups. In contrast, individual tests returned an ambiguous mixture of non-significant trends and significant effects for various outcome measures. Utilizing a range of behavioral measures and combining all outcome measure data to produce unified scores provides a useful tool for detecting subtle behavioral traits in preclinical models.
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http://dx.doi.org/10.3389/fnins.2020.00313DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7154181PMC
April 2020

The Efficacy of Sunitinib Treatment of Renal Cancer Cells Is Associated with the Protein PHAX In Vitro.

Biology (Basel) 2020 Apr 7;9(4). Epub 2020 Apr 7.

Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, UK.

Anti-angiogenic agents, such as the multi-tyrosine kinase inhibitor sunitinib, are key first line therapies for metastatic clear cell renal cell carcinoma (ccRCC), but their mechanism of action is not fully understood. Here, we take steps towards validating a computational prediction based on differential transcriptome network analysis that phosphorylated adapter RNA export protein (PHAX) is associated with sunitinib drug treatment. The regulatory impact factor differential network algorithm run on patient tissue samples suggests PHAX is likely an important regulator through changes in genome-wide network connectivity. Immunofluorescence staining of patient tumours showed strong localisation of PHAX to the microvasculature consistent with the anti-angiogenic effect of sunitinib. In normal kidney tissue, PHAX protein abundance was low but increased with tumour grade (G1 vs. G3/4; < 0.01), consistent with a possible role in cancer progression. In organ culture, ccRCC cells had higher levels of PHAX protein expression than normal kidney cells, and sunitinib increased PHAX protein expression in a dose dependent manner (untreated vs. 100 µM; < 0.05). PHAX knockdown in a ccRCC organ culture model impacted the ability of sunitinib to cause cancer cell death ( < 0.0001 untreated vs. treated), suggesting a role for PHAX in mediating the efficacy of sunitinib.
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http://dx.doi.org/10.3390/biology9040074DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7236799PMC
April 2020

Evaluation of the dual mTOR/PI3K inhibitors Gedatolisib (PF-05212384) and PF-04691502 against ovarian cancer xenograft models.

Sci Rep 2019 12 10;9(1):18742. Epub 2019 Dec 10.

Pathology, School of Medicine, University of St. Andrews, North Haugh, St. Andrews, Fife, KY16 9TF, United Kingdom.

This study investigated the antitumour effects of two dual mTOR/PI3K inhibitors, gedatolisib (WYE-129587/PKI-587/PF-05212384) and PF-04691502 against a panel of six human patient derived ovarian cancer xenograft models. Both dual mTOR/PI3K inhibitors demonstrated antitumour activity against all xenografts tested. The compounds produced tumour stasis during the treatment period and upon cessation of treatment, tumours re-grew. In several models, there was an initial rapid reduction of tumour volume over the first week of treatment before tumour stasis. No toxicity was observed during treatment. Biomarker studies were conducted in two xenograft models; phospho-S6 (Ser235/236) expression (as a readout of mTOR activity) was reduced over the treatment period in the responding xenograft but expression increased to control (no treatment) levels on cessation of treatment. Phospho-AKT (Ser473) expression (as a readout of PI3K) was inhibited by both drugs but less markedly so than phospho-S6 expression. Initial tumour volume reduction on treatment and regrowth rate after treatment cessation was associated with phospho-S6/total S6 expression ratio. Both drugs produced apoptosis but minimally influenced markers of proliferation (Ki67, phospho-histone H3). These results indicate that mTOR/PI3K inhibition can produce broad spectrum tumour growth stasis in ovarian cancer xenograft models during continuous chronic treatment and this is associated with apoptosis.
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http://dx.doi.org/10.1038/s41598-019-55096-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6904563PMC
December 2019

Letter--Value-Driven Treatment Decisions: Need of the Hour for Relapsed/Refractory Multiple Myeloma.

J Manag Care Spec Pharm 2019 Sep;25(9):1027-1028

Amgen, Thousand Oaks, CA.

Disclosures: No funding was involved in the writing of this letter. Medhekar, Sapra, Majer, Harrison, and Tekle are employees of and stockholders in Amgen.
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http://dx.doi.org/10.18553/jmcp.2019.25.9.1027DOI Listing
September 2019

The landscape of genomic copy number alterations in colorectal cancer and their consequences on gene expression levels and disease outcome.

Mol Aspects Med 2019 10 6;69:48-61. Epub 2019 Aug 6.

Gastrointestinal and Pancreatic Oncology Group, Institut D'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), CIBEREHD, Barcelona, Spain; Unitat de Biologia Cel·lular i Genètica Mèdica, Departament de Biologia Cel·lular, Fisiologia i Immunologia, Facultat de Medicina, Universitat Autònoma de Barcelona, Bellaterra, Spain. Electronic address:

Aneuploidy, the unbalanced state of the chromosome content, represents a hallmark of most solid tumors, including colorectal cancer. Such aneuploidies result in tumor specific genomic imbalances, which emerge in premalignant precursor lesions. Moreover, increasing levels of chromosomal instability have been observed in adenocarcinomas and are maintained in distant metastases. A number of studies have systematically integrated copy number alterations with gene expression changes in primary carcinomas, cell lines, and experimental models of aneuploidy. In fact, chromosomal aneuploidies target a number of genes conferring a selective advantage for the metabolism of the cancer cell. Copy number alterations not only have a positive correlation with expression changes of the majority of genes on the altered genomic segment, but also have effects on the transcriptional levels of genes genome-wide. Finally, copy number alterations have been associated with disease outcome; nevertheless, the translational applicability in clinical practice requires further studies. Here, we (i) review the spectrum of genetic alterations that lead to colorectal cancer, (ii) describe the most frequent copy number alterations at different stages of colorectal carcinogenesis, (iii) exemplify their positive correlation with gene expression levels, and (iv) discuss copy number alterations that are potentially involved in disease outcome of individual patients.
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http://dx.doi.org/10.1016/j.mam.2019.07.007DOI Listing
October 2019

A principled machine learning framework improves accuracy of stage II colorectal cancer prognosis.

NPJ Digit Med 2018 2;1:52. Epub 2018 Oct 2.

2School of Medicine, University of St Andrews, St Andrews, KY16 9TF UK.

Accurate prognosis is fundamental in planning an appropriate therapy for cancer patients. Consequent to the heterogeneity of the disease, intra- and inter-pathologist variability, and the inherent limitations of current pathological reporting systems, patient outcome varies considerably within similarly staged patient cohorts. This is particularly true when classifying stage II colorectal cancer patients using the current TNM guidelines. The aim of the present work is to address this problem through the use of machine learning. In particular, we introduce a data driven framework which makes use of a large number of diverse types of features, readily collected from immunofluorescence imagery. Its outstanding performance in predicting mortality in stage II patients (AUROC = 0:94), exceeds that of current clinical guidelines such as pT stage (AUROC = 0:65), and is demonstrated on a cohort of 173 colorectal cancer patients.
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http://dx.doi.org/10.1038/s41746-018-0057-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6550189PMC
October 2018

Novel Internationally Verified Method Reports Desmoplastic Reaction as the Most Significant Prognostic Feature For Disease-specific Survival in Stage II Colorectal Cancer.

Am J Surg Pathol 2019 09;43(9):1239-1248

Department of Surgery, National Defense Medical College, Saitama, Japan.

Multiple histopathologic features have been reported as candidates for predicting aggressive stage II colorectal cancer (CRC). These include tumor budding (TB), poorly differentiated clusters (PDC), Crohn-like lymphoid reaction and desmoplastic reaction (DR) categorization. Although their individual prognostic significance has been established, their association with disease-specific survival (DSS) has not been compared in stage II CRC. This study aimed to evaluate and compare the prognostic value of the above features in a Japanese (n=283) and a Scottish (n=163) cohort, as well as to compare 2 different reporting methodologies: analyzing each feature from across every tissue slide from the whole tumor and a more efficient methodology reporting each feature from a single slide containing the deepest tumor invasion. In the Japanese cohort, there was an excellent agreement between the multi-slide and single-slide methodologies for TB, PDC, and DR (κ=0.798 to 0.898) and a good agreement when assessing Crohn-like lymphoid reaction (κ=0.616). TB (hazard ratio [HR]=1.773; P=0.016), PDC (HR=1.706; P=0.028), and DR (HR=2.982; P<0.001) based on the single-slide method were all significantly associated with DSS. DR was the only candidate feature reported to be a significant independent prognostic factor (HR=2.982; P<0.001) with both multi-slide and single-slide methods. The single-slide result was verified in the Scottish cohort, where multivariate Cox regression analysis reported that DR was the only significant independent feature (HR=1.778; P=0.002) associated with DSS. DR was shown to be the most significant of all the analyzed histopathologic features to predict disease-specific death in stage II CRC. We further show that analyzing the features from a single-slide containing the tumor's deepest invasion is an efficient and quicker method of evaluation.
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http://dx.doi.org/10.1097/PAS.0000000000001304DOI Listing
September 2019

Genome-scale CRISPR/Cas9 screen determines factors modulating sensitivity to ProTide NUC-1031.

Sci Rep 2019 05 21;9(1):7643. Epub 2019 May 21.

School of Medicine, University of St Andrews, St Andrews, KY16 9TF, UK.

Gemcitabine is a fluoropyrimidine analogue that is used as a mainstay of chemotherapy treatment for pancreatic and ovarian cancers, amongst others. Despite its widespread use, gemcitabine achieves responses in less than 10% of patients with metastatic pancreatic cancer and has a very limited impact on overall survival due to intrinsic and acquired resistance. NUC-1031 (Acelarin), a phosphoramidate transformation of gemcitabine, was the first anti-cancer ProTide to enter the clinic. We find it displays important in vitro cytotoxicity differences to gemcitabine, and a genome-wide CRISPR/Cas9 genetic screening approach identified only the pyrimidine metabolism pathway as modifying cancer cell sensitivity to NUC-1031. Low deoxycytidine kinase expression in tumour biopsies from patients treated with gemcitabine, assessed by immunostaining and image analysis, correlates with a poor prognosis, but there is no such correlation in tumour biopsies from a Phase I cohort treated with NUC-1031.
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http://dx.doi.org/10.1038/s41598-019-44089-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6529431PMC
May 2019

Automated tumour budding quantification by machine learning augments TNM staging in muscle-invasive bladder cancer prognosis.

Sci Rep 2019 03 26;9(1):5174. Epub 2019 Mar 26.

School of Medicine, University of St Andrews, North Haugh, St Andrews, Fife, KY16 9TF, UK.

Tumour budding has been described as an independent prognostic feature in several tumour types. We report for the first time the relationship between tumour budding and survival evaluated in patients with muscle invasive bladder cancer. A machine learning-based methodology was applied to accurately quantify tumour buds across immunofluorescence labelled whole slide images from 100 muscle invasive bladder cancer patients. Furthermore, tumour budding was found to be correlated to TNM (p = 0.00089) and pT (p = 0.0078) staging. A novel classification and regression tree model was constructed to stratify all stage II, III, and IV patients into three new staging criteria based on disease specific survival. For the stratification of non-metastatic patients into high or low risk of disease specific death, our decision tree model reported that tumour budding was the most significant feature (HR = 2.59, p = 0.0091), and no clinical feature was utilised to categorise these patients. Our findings demonstrate that tumour budding, quantified using automated image analysis provides prognostic value for muscle invasive bladder cancer patients and a better model fit than TNM staging.
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http://dx.doi.org/10.1038/s41598-019-41595-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6435679PMC
March 2019

Automated Analysis of Lymphocytic Infiltration, Tumor Budding, and Their Spatial Relationship Improves Prognostic Accuracy in Colorectal Cancer.

Cancer Immunol Res 2019 04 7;7(4):609-620. Epub 2019 Mar 7.

Quantitative and Digital Pathology, School of Medicine, University of St. Andrews, St. Andrews, UK.

Both immune profiling and tumor budding significantly correlate with colorectal cancer patient outcome but are traditionally reported independently. This study evaluated the association and interaction between lymphocytic infiltration and tumor budding, coregistered on a single slide, in order to determine a more precise prognostic algorithm for patients with stage II colorectal cancer. Multiplexed immunofluorescence and automated image analysis were used for the quantification of CD3CD8 T cells, and tumor buds (TBs), across whole slide images of three independent cohorts (training cohort: = 114, validation cohort 1: = 56, validation cohort 2: = 62). Machine learning algorithms were used for feature selection and prognostic risk model development. High numbers of TBs [HR = 5.899; 95% confidence interval (CI) 1.875-18.55], low CD3 T-cell density (HR = 9.964; 95% CI, 3.156-31.46), and low mean number of CD3CD8 T cells within 50 μm of TBs (HR = 8.907; 95% CI, 2.834-28.0) were associated with reduced disease-specific survival. A prognostic signature, derived from integrating TBs, lymphocyte infiltration, and their spatial relationship, reported a more significant cohort stratification (HR = 18.75; 95% CI, 6.46-54.43), than TBs, Immunoscore, or pT stage. This was confirmed in two independent validation cohorts (HR = 12.27; 95% CI, 3.524-42.73; HR = 15.61; 95% CI, 4.692-51.91). The investigation of the spatial relationship between lymphocytes and TBs within the tumor microenvironment improves accuracy of prognosis of patients with stage II colorectal cancer through an automated image analysis and machine learning workflow.
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http://dx.doi.org/10.1158/2326-6066.CIR-18-0377DOI Listing
April 2019

Low-density lipoprotein cholesterol outcomes post-non-PCSK9i lipid-lowering therapies in atherosclerotic cardiovascular disease and probable heterozygous familial hypercholesterolemia patients.

Ther Clin Risk Manag 2018 13;14:2425-2435. Epub 2018 Dec 13.

IQVIA, Plymouth Meeting, PA, USA.

Background: This study evaluated the proportion of patients with atherosclerotic cardiovascular disease (ASCVD) and probable heterozygous familial hypercholesterolemia (HeFH) achieving ≥50% reduction in low-density lipoprotein cholesterol (LDL-C) or reaching the LDL-C ≤70 mg/dL threshold, after initiating or modifying statin, and/or ezetimibe therapy.

Materials And Methods: Adult ASCVD patients with baseline LDL-C >70 mg/dL (index) and a subset of patients with probable HeFH (proxied by LDL-C ≥190 mg/dL) were identified between January 1, 2012, and August 31, 2014, from the IQVIA electronic medical record database. Patients were followed for 12 months pre-index to examine baseline lipid-lowering therapy (LLT) use, and 12 months post index to evaluate treatment modifications and post-treatment LDL-C levels, stratified by type of treatment received and LDL-C levels at baseline.

Results: Of the sample of ASCVD patients who initiated treatment post-index (n=111,147), only 7.6% patients achieved a ≥50% reduction from baseline LDL-C and 19.1% of patients reached the LDL-C ≤70 mg/dL threshold. Among treated ASCVD patients who modified therapy post-index (n=75,523), 5.6% achieved a ≥50% reduction in LDL-C, and proportion of patients achieving LDL-C ≤70 mg/dL ranged from 6.9% to 26.7%, depending on the baseline LDL-C levels. Approximately 50% of the untreated probable HeFH patients (n=3,064) initiated LLT; however, the mean (SD) post-treatment LDL-C remained high (136.2 [47.8] mg/dL), with only 4.4% reaching LDL-C ≤70 mg/dL. Of the treated probable HeFH patients (n=1,073), 41.5% modified treatment; 22.1% achieved a ≥50% reduction in LDL-C and 1.1% reached LDL-C ≤70 mg/dL.

Conclusion: This study found that most patients had suboptimal LDL-C responses after initiating or modifying standard LLT (statin and/or ezetimibe). More frequent and aggressive lipid management, including increasing statin intensity and alternative therapies, may be needed in patients with ASCVD and probable HeFH to reduce their cardiovascular risk.
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http://dx.doi.org/10.2147/TCRM.S180783DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6296203PMC
December 2018

Treatment patterns and patient characteristics among early initiators of PCSK9 inhibitors.

Vasc Health Risk Manag 2018 10;14:409-418. Epub 2018 Dec 10.

Health Economics and Outcomes Research, IQVIA, Plymouth Meeting, PA, USA.

Purpose: To describe patient characteristics and treatment patterns among early initiators of proprotein convertase subtilisin/kexin type nine inhibitors (PCSK9is) who initiated treatment within the first 6 months of market availability.

Patients And Methods: This retrospective cohort study used IQVIA's longitudinal open-source point-of-sale pharmacy claims database (LRx) and PharMetrics Plus (P+) health plan claims database to identify patients initiating a PCSK9i between January 1, 2016 and June 30, 2016. The index date was defined as the date of the first PCSK9i prescription (index claim) during the enrollment window; patients were followed for ≥6 months postindex. Patient characteristics including use of baseline lipid-lowering therapy (LLT) and measures such as persistence and adherence to PCSK9i therapy were evaluated with respect to health plan type (commercial vs Medicare).

Results: Overall, patients initiating PCSK9i (n=13,151) had a mean age of 66 years, and 51% were male. Approximately 67.4% of patients used some form of LLT (statin and/or ezetimibe) in the 24 months prior to initiating PCSK9i therapy. The proportion of patients covered by a commercial health plan (51.2%) was similar to that covered by Medicare (48.8%). Persistence on PCSK9i was marginally longer for patients with commercial insurance than Medicare (mean days on therapy 202.2 vs 198.5). Overall, 42.6% of patients discontinued their PCSK9i during the 180 days of follow-up.

Conclusion: This study demonstrates that a large proportion of patients discontinue PCSK9i therapy at 30 and 90 days, which are the time frames for which many health plans require recertification to continue access to PCSK9i. Future studies looking at treatment patterns among patients who initiate PCSK9i therapy after the first 180 days once health plan formularies and utilization management criteria were finalized are needed to understand more comprehensively real-world PCSK9i usage patterns.
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http://dx.doi.org/10.2147/VHRM.S180496DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6292243PMC
January 2019

Identifying prognostic structural features in tissue sections of colon cancer patients using point pattern analysis.

Stat Med 2019 04 28;38(8):1421-1441. Epub 2018 Nov 28.

School of Arts, Media and Computer Games, Abertay University, UK.

Diagnosis and prognosis of cancer are informed by the architecture inherent in cancer patient tissue sections. This architecture is typically identified by pathologists, yet advances in computational image analysis facilitate quantitative assessment of this structure. In this article, we develop a spatial point process approach to describe patterns in cell distribution within tissue samples taken from colorectal cancer (CRC) patients. In particular, our approach is centered on the Palm intensity function. This leads to taking an approximate-likelihood technique in fitting point processes models. We consider two Neyman-Scott point processes and a void process, fitting these point process models to the CRC patient data. We find that the parameter estimates of these models may be used to quantify the spatial arrangement of cells. Importantly, we observe characteristic differences in the spatial arrangement of cells between patients who died from CRC and those alive at follow up.
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http://dx.doi.org/10.1002/sim.8046DOI Listing
April 2019

Medical Expenditures Among Medicare Beneficiaries with Statin-Associated Adverse Effects Following Myocardial Infarction.

Cardiovasc Drugs Ther 2018 12;32(6):601-610

Mount Sinai Heart, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Purpose: Compare medical expenditures among adults with statin-associated adverse effects (SAAE) and high statin adherence (HSA) following myocardial infarction (MI).

Methods: We analyzed expenditures in 2016 US dollars among Medicare beneficiaries with SAAE (n = 1741) and HSA (n = 55,567) who were ≥ 66 years of age and initiated moderate/high-intensity statins following an MI in 2007-2013. SAAE were identified through a claims-based algorithm, which included down-titrating statins and initiating ezetimibe, switching to ezetimibe monotherapy, having a rhabdomyolysis or antihyperlipidemic adverse event followed by statin down-titration or discontinuation, or switching between ≥ 3 statin types within 365 days following MI. HSA was defined by having a statin available to take for ≥ 80% of the days in the 365 days following MI.

Results: Expenditures among beneficiaries with SAAE and HSA were $40,776 (95% CI $38,329-$43,223) and $26,728 ($26,482-$26,974), respectively, in the 365 days following MI, and $34,238 ($31,396-$37,080) and $29,053 ($28,605-$29,500), respectively, for every year after the first 365 days. Multivariable-adjusted ratios comparing expenditures among beneficiaries with SAAE versus HSA in the first 365 days and after the first 365 days following MI were 1.51 (95% CI 1.43-1.59) and 1.23 (1.12-1.34), respectively. Inpatient and outpatient expenditures were higher among beneficiaries with SAAE versus HSA during and after the first 365 days following MI. Compared to beneficiaries with HSA, medication expenditures among those with SAAE were similar in the 365 days following MI, but higher afterwards. Other medical expenditures were higher among beneficiaries with SAAE versus HSA.

Conclusion: SAAE are associated with increased expenditures following MI compared with HSA.
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http://dx.doi.org/10.1007/s10557-018-6840-8DOI Listing
December 2018

Raman spectroscopy investigation of biochemical changes in tumor spheroids with aging and after treatment with staurosporine.

J Biophotonics 2019 05 9;12(5):e201800201. Epub 2019 Jan 9.

School of Chemistry, University of Edinburgh, Edinburgh, UK.

There has been increasing use of in vitro cell culture models that more realistically replicate the three-dimensional (3D) environment found in vivo. Multicellular tumor spheroids (MTS) using cell lines or patient-derived organoids have become an important in vitro drug development tool, where cells are grown in a 3D "sphere" that exhibits many of the characteristics found in vivo. Significantly, MTS develop gradients in nutrients and oxygen, commonly found in tumors that contribute to therapy resistance. While MTS show promise as a more realistic in vitro culture model, there is a massive need to improve imaging technologies for assessing biochemical characteristics and drug response in such models to maximize their translation into useful applications such as high throughput screening (HTS). In this study, we investigate the potential for Raman spectroscopy to unveil biochemical information in MTS and have investigated how spheroid age influences drug response, shedding light on increased therapy resistance in developing tumors. The wealth of molecular level information delivered by Raman spectroscopy in a noninvasive manner, could aid translation of these 3D models into HTS applications.
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http://dx.doi.org/10.1002/jbio.201800201DOI Listing
May 2019

Somatic cancer genetics in the UK: real-world data from phase I of the Cancer Research UK Stratified Medicine Programme.

ESMO Open 2018 5;3(6):e000408. Epub 2018 Sep 5.

Cancer Research UK, London, UK.

Introduction: Phase I of the Cancer Research UK Stratified Medicine Programme (SMP1) was designed to roll out molecular pathology testing nationwide at the point of cancer diagnosis, as well as facilitate an infrastructure where surplus cancer tissue could be used for research. It offered a non-trial setting to examine common UK cancer genetics in a real-world context.

Methods: A total of 26 sites in England, Wales and Scotland, recruited samples from 7814 patients for genetic examination between 2011 and 2013. Tumour types involved were breast, colorectal, lung, prostate, ovarian cancer and malignant melanoma. Centralised molecular testing of surplus material from resections or biopsies of primary/metastatic tissue was performed, with samples examined for 3-5 genetic alterations deemed to be of key interest in site-specific cancers by the National Cancer Research Institute Clinical Study groups.

Results: 10 754 patients (98% of those approached) consented to participate, from which 7814 tumour samples were genetically analysed. In total, 53% had at least one genetic aberration detected. From 1885 patients with lung cancer, mutation was noted to be highly prevalent in adenocarcinoma (37%). In breast cancer (1873 patients), there was a striking contrast in mutation incidence between patients with ductal cancer (27.3%) and lobular cancer (3.4%). Vast inter-tumour heterogeneity of colorectal cancer (1550 patients) was observed, including myriad double and triple combinations of genetic aberrations. Significant losses of important clinical information included smoking status in lung cancer and loss of distinction between low-grade and high-grade serous ovarian cancers.

Conclusion: Nationwide molecular pathology testing in a non-trial setting is feasible. The experience with SMP1 has been used to inform ongoing CRUK flagship programmes such as the CRUK National Lung MATRIX trial and TRACERx.
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http://dx.doi.org/10.1136/esmoopen-2018-000408DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6135448PMC
September 2018

Disease-modifying antirheumatic drug initiation among patients newly diagnosed with rheumatoid arthritis.

Am J Manag Care 2018 07;24(8 Spec No.):SP279-SP285

Truven Health Analytics, an IBM Company, 75 Binney St, Cambridge, MA 02142. Email:

Objectives: To determine the rate of timely disease-modifying antirheumatic drug (DMARD) initiation in patients newly diagnosed with rheumatoid arthritis (RA), as recommended per a quality measure endorsed by the National Quality Forum.

Study Design: Retrospective analysis of claims data from the Truven Health MarketScan commercial and Medicare claims databases.

Methods: Patients newly diagnosed with RA were identified in the claims databases. Outcomes included rate of nonbiologic or biologic DMARD initiation within 12 months of diagnosis; initiation by year (2009-2012), US state, and prescription drug plan; and time to initiation. Multivariate modeling was performed to identify factors associated with initiation or noninitiation.

Results: Of 40,040 newly diagnosed patients, 55.5% initiated RA therapy within 12 months, including 21,154 (52.8%) initiating DMARD therapy and 1051 (2.6%) initiating biologic DMARD therapy. Rates were similar for years 2009 (53.3%), 2010 (55.7%), 2011 (56.3%), and 2012 (56.8%), but they varied widely by US state (range, 33.3%-88.0%) and prescription plan (range, 42.6%-63.5% across 8 largest plans). Mean (SD) time to initiation of any RA therapy was 39 (65) days. Predictors of initiation included point-of-service (odds ratio [OR], 1.18) and consumer-driven/high-deductible (OR, 1.19) plans, comorbid psoriasis (OR, 1.30) or diabetes (OR, 1.17), rheumatoid factor test (OR, 3.02), and diagnosis by a rheumatologist (OR, 3.17). Predictors of noninitiation included female sex (OR, 0.94), preferred provider organization plan (OR, 0.87), higher comorbidity score (OR, 0.94), select comorbidities (OR range, 0.65-0.92), and number of prescriptions for any cause (OR, 0.98).

Conclusions: Only slightly more than half of patients initiated RA therapy within 12 months of diagnosis in this commercially insured population.
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July 2018

Podocyte injury elicits loss and recovery of cellular forces.

Sci Adv 2018 06 27;4(6):eaap8030. Epub 2018 Jun 27.

School of Medicine, University of St Andrews, St Andrews KY16 9TF, UK.

In the healthy kidney, specialized cells called podocytes form a sophisticated blood filtration apparatus that allows excretion of wastes and excess fluid from the blood while preventing loss of proteins such as albumin. To operate effectively, this filter is under substantial hydrostatic mechanical pressure. Given their function, it is expected that the ability to apply mechanical force is crucial to the survival of podocytes. However, to date, podocyte mechanobiology remains poorly understood, largely because of a lack of experimental data on the forces involved. We perform quantitative, continuous, nondisruptive, and high-resolution measurements of the forces exerted by differentiated podocytes in real time using a recently introduced functional imaging modality for continuous force mapping. Using an accepted model for podocyte injury, we find that injured podocytes experience near-complete loss of cellular force transmission but that this loss of force is reversible under certain conditions. The observed changes in force correlate with F-actin rearrangement and reduced expression of podocyte-specific proteins. By introducing robust and high-throughput mechanical phenotyping and by demonstrating the significance of mechanical forces in podocyte injury, this research paves the way to a new level of understanding of the kidney. In addition, in an advance over established force mapping techniques, we integrate cellular force measurements with immunofluorescence and perform continuous long-term force measurements of a cell population. Hence, our approach has general applicability to a wide range of biomedical questions involving mechanical forces.
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http://dx.doi.org/10.1126/sciadv.aap8030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6021140PMC
June 2018
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