Assessment of deep learning-based reconstruction on T2-weighted and diffusion-weighted prostate MRI image quality.

PURPOSE: To evaluate the impact of a commercially available deep learning-based reconstruction (DLR) algorithm with varying combinations of DLR noise reduction settings and imaging parameters on quantitative and qualitative image quality, PI-RADS classification and examination time in prostate T2-weighted (T2WI) and diffusion-weighted (DWI) imaging. METHOD: Forty patients were included. Standard-of-care (SoC) prostate MRI sequences including T2WI and DWI were reconstructed without and with different DLR de-noising levels (low, medium, high). In addition, faster T2WI(Fast) and DWI(Fast) sequences, and a higher resolution T2WI(HR) sequence were evaluated. Quantitative analysis included signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR) and apparent diffusion coefficient (ADC) values. Two radiologists performed qualitative analysis, independently evaluating imaging datasets using 5-point scoring scales for image quality and artifacts. PI-RADS category assignment was also performed by the more experienced radiologist. RESULTS: All DLR levels resulted in significantly higher SNR and CNR compared to the DLR(off) acquisitions. DLR allowed the acquisition time to be reduced by 33% for T2WI(Fast) and 49% for DWI(Fast) compared to SoC, without affecting image quality, whilst T2WI(HR) with DLR allowed for a 73% increase in spatial resolution in the phase encode direction compared to SoC. The inter-reader agreement for image quality and artifact scores was substantial for all subjective measurements on T2WI and DWI. The T2WI(Fast) protocol with DLR(medium) and DWI(Fast) with DLR(low) received the highest qualitative quality score. CONCLUSION: DLR can reduce T2WI and DWI acquisition time and increase SNR and CNR without compromising image quality or altering PI-RADS classification.

Real-world evidence from the first online healthcare analytics platform-Livingstone. Validation of its descriptive epidemiology module.

Incidence and prevalence are key epidemiological determinants characterizing the quantum of a disease. We compared incidence and prevalence estimates derived automatically from the first ever online, essentially real-time, healthcare analytics platform-Livingstone-against findings from comparable peer-reviewed studies in order to validate the descriptive epidemiology module. The source of routine NHS data for Livingstone was the Clinical Practice Research Datalink (CPRD). After applying a general search strategy looking for any disease or condition, 76 relevant studies were first retrieved, of which 10 met pre-specified inclusion and exclusion criteria. Findings reported in these studies were compared with estimates produced automatically by Livingstone. The published reports described elements of the epidemiology of 14 diseases or conditions. Lin's concordance correlation coefficient (CCC) was used to evaluate the concordance between findings from Livingstone and those detailed in the published studies. The concordance of incidence values in the final year reported by each study versus Livingstone was 0.96 (95% CI: 0.89-0.98), whilst for all annual incidence values the concordance was 0.93 (0.91-0.94). For prevalence, concordance for the final annual prevalence reported in each study versus Livingstone was 1.00 (0.99-1.00) and for all reported annual prevalence values, the concordance was 0.93 (0.90-0.95). The concordance between Livingstone and the latest published findings was near perfect for prevalence and substantial for incidence. For the first time, it is now possible to automatically generate reliable descriptive epidemiology from routine health records, and in near-real time. Livingstone provides the first mechanism to rapidly generate standardised, descriptive epidemiology for all clinical events from real world data.

A Phase 1 First-in-Human Study of FS118, a Tetravalent Bispecific Antibody Targeting LAG-3 and PD-L1 in Patients with Advanced Cancer and PD-L1 Resistance.

PURPOSE: This phase 1 study (NCT03440437) evaluated the safety, tolerability, pharmacokinetics (PK), and activity of FS118, a bispecific antibody-targeting LAG-3 and PD-L1, in patients with advanced cancer resistant to anti-PD-(L)1 therapy. PATIENTS AND METHODS: Patients with solid tumors, refractory to anti-PD-(L)1-based therapy, received intravenous FS118 weekly with an accelerated dose titration design (800 µg to 0.3 mg/kg) followed by 3+3 ascending dose expansion (1 to 20 mg/kg). Primary objectives were safety, tolerability, and PK. Additional endpoints included antitumor activity, immunogenicity, and pharmacodynamics. RESULTS: Forty-three patients with a median of three prior regimens in the locally advanced/metastatic setting, including at least one anti-PD-(L)1 regimen, received FS118 monotherapy. FS118 was well tolerated, with no serious adverse events relating to FS118 reported. No dose-limiting toxicities (DLT) were observed, and an MTD was not reached. The recommended phase 2 dose of FS118 was established as 10 mg/kg weekly. The terminal half-life was 3.9 days. Immunogenicity was transient. Pharmacodynamic activity was prolonged throughout dosing as demonstrated by sustained elevation of soluble LAG-3 and increased peripheral effector cells. The overall disease control rate (DCR) was 46.5%; this disease control was observed as stable disease, except for one late partial response. Disease control of 54.8% was observed in patients receiving 1 mg/kg or greater who had acquired resistance to PD-(L)1-targeted therapy. CONCLUSIONS: FS118 was well tolerated with no DLTs observed up to and including 20 mg/kg QW. Further studies are warranted to determine clinical benefit in patients who have become refractory to anti-PD-(L)1 therapy. See related commentary by Karapetyan and Luke, p. 835.

Durable response of anaplastic thyroid carcinoma to FS118, a bispecific LAG-3/PD-L1 antibody, after checkpoint inhibitor progression: a case report.

Anaplastic thyroid cancer represents a rare, highly aggressive form of thyroid cancer with a poor prognosis and an overall survival ranging from 5 to 12 months. Unfortunately, treatment options remain limited, even for patients with a targetable driver mutation. Here, we present a case of a patient with a BRAF V600E-mutated, PD-L1 positive (tumor proportion score of 95%) anaplastic thyroid cancer refractory to standard therapies, including debulking surgery, followed by chemoradiation, who had further progressed on PD-1 monotherapy, and was unable to tolerate BRAF/MEK inhibition. Ongoing treatment with FS118, a bispecific LAG-3/PD-L1 antagonist, has afforded 3 years of disease control, including a late confirmed partial response, with excellent tolerability. Given this response, further investigation is required to delineate the mechanism by which dual PD-L1/LAG-3 blockade by FS118 overcomes initial PD-1 pathway resistance, and therefore, identify which patients are most likely to benefit. Simultaneously, expanded use should be considered for those with refractory disease, especially if PD-L1 positive. Insights Dual PD-L1/LAG-3 blockade may be an effective treatment strategy for refractory metastatic tumors, including anaplastic thyroid cancer.

Disease Control Attributes of Oxathiapiprolin Fungicides for Management of Cucurbit Downy Mildew.

Oxathiapiprolin, a novel oomycete fungicide recently registered by DuPont, was reported to have high intrinsic activity against cucurbit downy mildew (Pseudoperonospora cubensis). The goal of this study was to characterize disease control attributes of oxathiapiprolin-based fungicides critical to effective management of cucurbit downy mildew. In growth chamber and greenhouse studies, oxathiapiprolin-based fungicides were compared with mandipropamid, mefenoxam + mancozeb, fluopicolide + propamocarb, cymoxanil + mancozeb, and ametoctradin + dimethomorph products for pre- and postinfection activity, local systemic movement, and protection of new growth produced after fungicide application. In preventive application, oxathiapiprolin-based fungicides significantly (P < 0.0001) inhibited downy mildew development, with the highest level of disease observed being 0.4% compared with 86.7% observed for mandipropamid. When applied postinfection, oxathiapiprolin-based fungicides significantly (P < 0.0001) suppressed disease development, but disease control was reduced relative to that observed for preventive application. There was a significant effect of formulation on the postinfection activity of oxathiapiprolin, whereby the oil dispersion (OD) formulation was more inhibitory than the water-dispersible granule formulation (0.001 ≤ P ≤ 0.049). Disease severity on the outer half leaf portion protected from spray deposition during fungicide application was lower for oxathiapiprolin-based fungicides (1.6 to 6.6%) than observed for fluopicolide + propamocarb (10.9 to 23.7%), mefenoxam + mancozeb (40.3 to 51.4%), and the nontreated controls (83.3 to 84.9%), which indicates significant acropetal movement within the leaf. Postinfection applications of oxathiapiprolin-based formulations had the greatest effect on lesion growth and sporangia production compared with the other fungicides in the experiment. When applied preventively to rapidly growing plants in a greenhouse, oxathiapiprolin-based fungicides consistently protected new growth that was not present at the time of application, with the OD formulation reducing disease severity by >75% relative to nontreated plants. The practical implications of these observations are discussed.

Fulvestrant Plus Vistusertib vs Fulvestrant Plus Everolimus vs Fulvestrant Alone for Women With Hormone Receptor-Positive Metastatic Breast Cancer: The MANTA Phase 2 Randomized Clinical Trial.

IMPORTANCE: Randomized clinical trials have demonstrated a substantial benefit of adding everolimus to endocrine therapy. Everolimus inhibits the mammalian target of rapamycin complex 1 (mTORC1) complex but not mTORC2, which can set off an activating feedback loop via mTORC2. Vistusertib, a dual inhibitor of mTORC1 and mTORC2, has demonstrated broad activity in preclinical breast cancer models, showing superior activity to everolimus. OBJECTIVE: To evaluate the safety and efficacy of vistusertib in combination with fulvestrant compared with fulvestrant alone or fulvestrant plus everolimus in postmenopausal women with estrogen receptor-positive advanced or metastatic breast cancer. DESIGN, SETTING, AND PARTICIPANTS: The MANTA trial is an open-label, phase 2 randomized clinical trial in which 333 patients with estrogen receptor-positive breast cancer progressing after prior aromatase inhibitor treatment underwent randomization (2:3:3:2) between April 1, 2014, and October 24, 2016, at 88 sites in 9 countries: 67 patients were assigned to receive fulvestrant, 103 fulvestrant plus vistusertib daily, 98 fulvestrant plus vistusertib intermittently, and 65 fulvestrant plus everolimus. Treatment was continued until disease progression, development of unacceptable toxic effects, or withdrawal of consent. Analysis was performed on an intention-to-treat basis. INTERVENTIONS: Fulvestrant alone or in combination with vistusertib (continuous or intermittent dosing schedules) or everolimus. MAIN OUTCOMES AND MEASURES: The primary end point was progression-free survival (PFS). RESULTS: Among the 333 women in the study (median age, 63 years [range, 56-70 years]), median PFS was 5.4 months (95% CI, 3.5-9.2 months) with fulvestrant, 7.6 months (95% CI, 5.9-9.4 months) with fulvestrant plus daily vistusertib, 8.0 months (95% CI, 5.6-9.9 months) with fulvestrant plus intermittent vistusertib, and 12.3 months (95% CI, 7.7-15.7 months) with fulvestrant plus everolimus. There was no significant difference in PFS between those receiving fulvestrant plus daily or intermittent vistusertib and fulvestrant alone (hazard ratio, 0.88 [95% CI, 0.63-1.24]; P = .46; and hazard ratio, 0.79 [95% CI, 0.55-1.12]; P = .16). CONCLUSIONS AND RELEVANCE: The combination of fulvestrant plus everolimus demonstrated significantly longer PFS compared with fulvestrant plus vistusertib or fulvestrant alone. The trial failed to demonstrate a benefit of adding the dual mTORC1 and mTORC2 inhibitor vistusertib to fulvestrant. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02216786 and EudraCT number: 2013-002403-34.

Distinct roles for miR-1 and miR-133a in the proliferation and differentiation of rhabdomyosarcoma cells.

Rhabdomyosarcoma is the most common soft tissue sarcoma in the pediatric population. As this tumor has an undifferentiated myogenic phenotype, agents that promote differentiation hold particular promise as part of a novel therapeutic approach to combat this type of cancer. In this report, we focus on the contribution of two microRNAs (miRNAs) in rhabdomyosarcomas. Levels of miR-1 and miR-133a are drastically reduced in representative cell lines from each major rhabdomyosarcoma subtype (embryonal and alveolar). Introduction of miR-1 and miR-133a into an embryonal rhabdomyosarcoma-derived cell line is cytostatic, thereby suggesting a tumor suppressor-like role for these myogenic miRNAs. Transcriptional profiling of cells after miR-1 and miR-133a expression reveals that miR-1 (but not miR-133a) exerts a strong promyogenic influence on these poorly differentiated tumor cells. We identify mRNAs that are down-regulated by these miRNAs and propose roles for miR-1 and miR-133a in repressing isoforms of genes that are normally not expressed in muscle. Finally, we show that mRNA targets of miR-1 and miR-133a are up-regulated in rhabdomyosarcomas, suggesting a causative role for these miRNAs in the development of rhabdomyosarcomas. More important, these results point to the promise of enhancing rhabdomyosarcoma therapy using miRNAs as agents that mediate cytostasis and promote muscle differentiation.

Integration of ERG gene mapping and gene-expression profiling identifies distinct categories of human prostate cancer.

OBJECTIVE: To integrate the mapping of ERG alterations with the collection of expression microarray (EMA) data, as previous EMA analyses have failed to consider the genetic heterogeneity and complex patterns of ERG alteration frequently found in cancerous prostates. MATERIALS AND METHODS: We determined genome-wide expression levels with GeneChip Human Exon 1.0 ST arrays (Affymetrix, Santa Clara, CA, USA) using RNA prepared from 35 specimens of prostate cancer from 28 prostates. RESULTS: The expression profiles showed clustering, in unsupervised hierarchical analyses, into two distinct prostate cancer categories, with one group strongly associated with indicators of poor clinical outcome. The two categories are not tightly linked to ERG status. By analysis of the data we identified a subgroup of cancers lacking ERG rearrangements that showed an outlier pattern of SPINK1 mRNA expression. There was a major distinction between ERG rearranged and non-rearranged cancers that involves the levels of expression of genes linked to exposure to beta-oestradiol, and to retinoic acid. CONCLUSIONS: Expression profiling of prostate cancer samples containing single patterns of ERG alterations can provide novel insights into the mechanism of prostate cancer development, and support the view that factors other than ERG status are the major determinants of poor clinical outcome.

Expression profiling of CD133+ and CD133- epithelial cells from human prostate.

BACKGROUND: Recent evidence suggests that prostate stem cells in benign and tumor tissue express the cell surface marker CD133, but these cells have not been well characterized. The aim of our study was to gene expression profile CD133-expressing cells. METHODS: We analyzed CD133-positive (CD133+) and -negative (CD133-) sub-populations of high-integrin expressing epithelial cells isolated from benign human prostate tissue and hormone-refractory prostate cancer (HRPC). RESULTS: CD133+ cells freshly isolated from benign prostate tissue exhibited an expression profile characteristic of a putative stem/progenitor cell population, with transcripts involved in biological processes ranging from development and ion homeostasis to cell communication. The profile of CD133- cells was consistent with that of a transit amplifying population, suggesting up-regulated proliferation and metabolism. Comparison of benign populations to those from HRPC showed some similarities between CD133+ profiles but also revealed significant differences that provide a tumor-specific pattern, which included evidence of increased metabolic activity and active proliferation. Subsequently, we demonstrated protein expression of a number of candidate genes in these cell populations and in benign tissue. In a novel observation we also found expression of some of these markers in prostate tumors, including the oligodendrocyte lineage transcription factor OLIG1. CONCLUSIONS: This study provides a unique genome-wide molecular signature of CD133+ and CD133- human prostate epithelial cells. This will provide a valuable resource for prostate stem cell biology research and the identification of novel therapeutic targets for the treatment of prostate cancer.

A conditionally immortalized cell line model for the study of human prostatic epithelial cell differentiation.

In the normal human prostate, undifferentiated proliferative cells reside in the basal layer and give rise to luminal secretory cells. There are, however, few epithelial cell lines that have a basal cell phenotype and are able to differentiate. We set out to develop a cell line with these characteristics that would be suitable for the study of the early stages of prostate epithelial cell differentiation. We produced a matched pair of conditionally immortalized prostate epithelial and stromal cell lines derived from the same patient. The growth of these cells is temperature dependent and differentiation can be induced following a rise in culture temperature. Three-dimensional co-cultures of these cell lines elicited gland-like structures reminiscent of prostatic acini. cDNA microarray analysis of the epithelial line demonstrated changes in gene expression consistent with epithelial differentiation. These genes may prove useful as markers for different prostate cell types. The cell lines provide a model system with which to study the process of prostatic epithelial differentiation and stromal-epithelial interactions. This may prove to be useful in the development of differentiation-targeted prostate cancer therapies.

Polymorphism at the C-reactive protein locus influences gene expression and predisposes to systemic lupus erythematosus.

Relative deficiency of pentraxin proteins is implicated in the pathogenesis of systemic lupus erythematosus. The C-reactive protein (CRP) response is defective in patients with acute flares of disease, and mice with targeted deletions of the serum amyloid P component gene (Sap) develop a lupus-like illness. In humans, the genes for CRP (CRP) and SAP (APCS) map to 1q23.2 within an interval linked with SLE. We have investigated the candidate genes CRP and APCS in two cohorts totalling 586 UK simplex SLE families. The inheritance of an intronic dinucleotide repeat and seven single nucleotide polymorphisms in the CRP and APCS genes was examined by application of family-based tests of association and linkage. Basal levels of CRP were influenced independently by two polymorphisms at the CRP locus, CRP 2 and CRP 4. Furthermore, the latter polymorphism was linked/associated with SLE and antinuclear autoantibody production. Thus, the polymorphism associated with reduced basal CRP was also associated with the development of SLE. These data support the hypothesis that defective disposal of potentially immunogenic material is a contributory factor in lupus pathogenesis. The identification of polymorphisms that determine basal CRP levels has implications in ischaemic heart disease, where CRP level is an important predictor of risk.