Visualizing features with wide-field volumetric OCT angiography.

Optical coherence tomography (OCT) and its extension OCT angiography (OCTA) have become essential clinical imaging modalities due to their ability to provide depth-resolved angiographic and tissue structural information non-invasively and at high resolution. Within a field of view, the anatomic detail available is sufficient to identify several structural and vascular pathologies that are clinically relevant for multiple prevalent blinding diseases, including age-related macular degeneration (AMD), diabetic retinopathy (DR), and vein occlusions. The main limitation in contemporary OCT devices is that this field of view is limited due to a fundamental trade-off between system resolution/sensitivity, sampling density, and imaging window dimensions. Here, we describe a swept-source OCT device that can capture up to a 12 × 23-mm field of view in a single shot and show that it can identify conventional pathologic features such as non-perfusion areas outside of conventional fields of view. We also show that our approach maintains sensitivity sufficient to visualize novel features, including choriocapillaris morphology beneath the macula and macrophage-like cells at the inner limiting membrane, both of which may have implications for disease.

Regulatory Review Duration and Differences in Submission Times of Drugs in the United States and Europe, 2011 to 2020.

The speed of drug regulatory agencies in the United States and Europe is often a source of discussion. The objective of this research was to assess regulatory review duration of first and supplementary indications approved between 2011 and 2020 in the United States and Europe (European Union [EU] and Switzerland) and differences in submission times between the United States and Europe. Descriptive statistics were applied to review times between the jurisdictions and across the therapeutic areas. A regression analysis was done to estimate the association between approval agency and review times. The primary analysis cohort included 241 drugs approved in the United States, the EU, and Switzerland. Of these, 128 drugs had supplemental indications (331 in total) in the United States and 87 had supplemental indications (206 in total) in the EU. Overall median review duration from submission to approval subtracting the clock stop period was 39 weeks in the United States, 44 weeks in the EU, and 44 weeks in Switzerland. When review times within each drug were compared, the European Medicines Agency took a median of 3.7 weeks (IQR, -6.7 to 14.9 weeks) longer than the U.S. Food and Drug Administration and Swissmedic a median of 0.3 weeks (IQR, -10.6 to 15.3 weeks) longer. Median total review duration for supplemental indications was 26 weeks in the United States and 40 weeks in the EU. Applications were submitted a median of 1.3 and 17.9 weeks later in the EU and Switzerland, respectively, than in the United States. The regression analysis showed small differences in submission times between the United States and the EU (-2.1 weeks [95% CI, -11.7 to 7.6 weeks]) and larger differences between the United States and Switzerland (33.0 weeks [CI, 23.1 to 42.8 weeks]). It would be beneficial for patients if differences in submission times between the United States and Europe continue to be minimized.

Price changes and within-class competition of cancer drugs in the USA and Europe: a comparative analysis.

BACKGROUND: Cancer drugs are a major component of pharmaceutical spending in the USA and Europe. The number of approved cancer drugs continues to increase. More new drugs with overlapping mechanisms of action and similar approved indications might be expected to decrease prices within drug classes. We compared patterns of price changes for cancer drugs within the same class in the USA and in two European countries (Germany and Switzerland) with national mechanisms for drug price negotiation. METHODS: For this comparative analysis, we identified cancer drugs approved for the treatment of solid cancers in the USA and Europe (Germany and Switzerland) between Jan 1, 2009, and Dec 31, 2020, using the US Food and Drug Administration's Drugs@FDA database and the European Medicines Agency's publicly available database. We considered cancer drugs as within-class competitors if they were approved for the same indication and had the same biological mechanism. We calculated monthly treatment prices for each drug, median price changes at launch and over time, and differences within and across drug classes. European price data were converted to US dollars by applying the exchange rates on Dec 1, 2020, and prices were adjusted for inflation. Median changes in the drugs' monthly treatment prices at 2 and 4 years after market entry across and within drug classes were also assessed. For the USA, correlations in relative price changes between all pairs of drugs within and across drug classes were calculated with Spearman's rank correlation. FINDINGS: Our study cohort comprised 12 drug classes covering nine indications. With the exception of one drug, increasing prices were observed within and across all drug classes in the USA (median 6·07% [range -3·60 to 33·83] 2 years after market entry, and 15·31% [-4·15 to 54·64] 4 years after market entry). By contrast, in Europe, prices generally decreased over time or did not increase more than inflation (2 years after market entry: -21·01% [range -50·72 to 12·71] in Germany and -1·48% [-26·81 to 1·69] in Switzerland; 4 years after market entry: -25·54% [-51·81 to 11·63] in Germany and -13·02% [-43·83 to 18·31] in Switzerland). In the USA, most prices changes within and across drug classes occurred at the end and beginning of the year (ie, from Dec 1 to Jan 31). In the USA, correlation for price changes was r=0·29 (SD 0·36) for within-class drugs and r=0·28 (0·36) for drugs across drug classes. INTERPRETATION: Competition within classes of cancer drugs generally did not constrain rising prices in the USA. Price negotiations, as practised in Germany or Switzerland, could help address the high prices of cancer drugs in the USA. FUNDING: Swiss Cancer Research Foundation (Krebsforschung Schweiz), Swiss National Science Foundation, and Arnold Ventures.

Autophagy blockade potentiates cancer-associated immunosuppression through programmed death ligand-1 upregulation in bladder cancer.

A high basal level of autophagic flux in bladder cancer (BC) cells prevents cell death and weakens chemotherapy efficacy. However, how autophagy influences cancer-associated immunosuppression in BC remains undetermined. In this study, we observed a negative correlation between the autophagy-related markers LC3-II and programmed death ligand-1 (PD-L1) in BC cells. The autophagy inhibitors chloroquine (CQ) and bafilomycin A1 (Baf-A1) increased PD-L1 expression in BC cells through the ERK-JNK-c-Jun signal-transduction pathway. Moreover, the treatment of BC cells with CQ and Baf-A1 inhibited hsa-microRNA-34a (miR-34a) expression and miR-34a overexpression in BC cells prevented the autophagy blockade-induced PD-L1 expression; a negative correlation between miR-34a and PD-L1 expression was observed during treatment with autophagy inhibitors. Furthermore, miR-34a overexpression induced the cytotoxic activity of natural killer cells against BC cells. Our results provide evidence that autophagy blockade and its regulatory pathway affect cancer-associated immunosuppression through PD-L1 elevation. Thus, the coadministration of autophagy inhibitors and a PD-L1 immune checkpoint blockade provides a potential therapeutic approach for treating BC.

Coverage of New Drugs in Medicare Part D.

Policy Points Only a small minority of new drugs in "nonprotected" classes are widely covered by Part D plans nationwide in the year after US Food and Drug Administration (FDA) approval. Part D plans frequently apply utilization management restrictions such as prior authorizations to newly approved drugs in both protected and nonprotected classes. Drug price influences both formulary inclusion (in nonprotected classes) and coverage restrictions (in both protected and nonprotected classes), while other drug characteristics such as therapeutic benefits are not consistently associated with formulary design. Plans do not seem to favor the minority of drugs that are determined to offer added therapeutic benefit over existing alternatives. CONTEXT: Medicare Part D is an outpatient prescription drug benefit for older Americans covering more than 46 million beneficiaries. Except for mandatory coverage for essentially all drugs in six protected classes, plans have substantial flexibility in how they design their formularies: which drugs are covered, which drugs are subject to restrictions, and what factors determine formulary placement. Our objective in this paper was to document the extent to which Part D plans limit coverage of newly approved drugs. METHODS: We examined the formulary design of 4,582 Part D plans from 2014 through 2018 and measured (1) the decision to cover newly approved drugs in nonprotected classes, (2) use of utilization management tools in protected and nonprotected classes, and (3) the association between plan design and drug-level characteristics such as 30-day cost, therapeutic benefit, and the US Food and Drug Administration (FDA) expedited regulatory pathway. FINDINGS: The FDA approved 109 new drugs predominantly used in outpatient settings between 2013 and 2017. Of these, 75 fell outside of the six protected drug classes. One-fifth of drugs in nonprotected classes (15 out of 75) were covered by more than half of plans during the first year after approval. Coverage was often conditional on utilization management strategies in both protected and nonprotected classes: only seven drugs (6%) were covered without prior authorization requirements in more than half of plans. Higher 30-day drug costs were associated with more widespread coverage in nonprotected classes: drugs that cost less than $150 for a 30-day course were covered by fewer than 20% of plans while those that cost more than $30,000 per 30 days were covered by more than 50% of plans. Plans were also more likely to implement utilization management tools on high-cost drugs in both protected and nonprotected classes. A higher proportion of plans implemented utilization management strategies on covered drugs with first-in-class status than drugs that were not first in class. Other drug characteristics, including availability of added therapeutic benefit and inclusion in FDA expedited regulatory approval, were not consistently associated with plan coverage or formulary restrictions. CONCLUSIONS: Newly approved drugs are frequently subject to formulary exclusions and restrictions in Medicare Part D. Ensuring that formulary design in Part D is linked closely to the therapeutic value of newly approved drugs would improve patients' welfare.

THREE-DIMENSIONAL QUANTIFICATION OF INTRARETINAL CYSTOID SPACES ASSOCIATED WITH FULL-THICKNESS MACULAR HOLE.

PURPOSE: To evaluate intraretinal cystoid spaces in patients with idiopathic macular hole (MH). METHODS: Retrospective cohort study included consecutive patients with full-thickness MH who underwent successful MH surgery and 12 months of follow-up. Custom software was applied to preoperative optical coherence tomography scans to generate fluid volume. Inner fluid volume was defined as cystoid spaces in the inner nuclear layer, and outer fluid volume was defined as cystoid spaces in Henle fiber layer of the outer nuclear layer. RESULTS: Thirty-nine eyes from 39 participants were included. Postoperative 12-month visual acuity correlated with both inner fluid volume and minimum MH size (both P < 0.05) but not outer fluid volume. Inner fluid volume positively correlated with minimum MH size ( P = 0.0003). After accounting for minimum MH size with multivariable analysis, inner fluid volume effect on VA remained significant ( P = 0.025). After dividing inner fluid volume into tertiles, mean baseline visual acuity was 20/50 in eyes with small inner fluid volume, and was 20/125 in eyes with large inner fluid volume ( P = 0.0039). Mean postoperative 12-month visual acuity was 20/20 in eyes with small inner fluid volume compared with 20/32 in eyes with large inner fluid volume ( P = 0.019). CONCLUSION: Increased inner fluid volume was associated with worse postoperative VA.

Thrombospondin-4 promotes bladder cancer cell migration and invasion via MMP2 production.

Bladder cancer (BC) is the second most common urological tumour in Western countries. Approximately, 80% of patients with BC will present with non-muscle invasive bladder cancer (NMIBC), whereas a quarter will have muscle invasive disease (MIBC) at the time of BC diagnosis. However, patients with NMIBC are at risk of BC recurrence or progression into MIBC, and an MIBC prognosis is determined by the presence of progression and metastasis. Matrix metalloproteinase 2 (MMP2), a type of matrix metalloproteinase (MMP), plays a major role in tumour invasion and is well-characterized in BC prognosis. In BC, the mechanisms regulating MMP2 expression, and, in turn, promote cancer invasion, have hardly been explored. Thrombospondin-4 (THBS4/TSP4) is a matricellular glycoprotein that regulates multiple biological functions, including proliferation, angiogenesis, cell adhesion and extracellular matrix modelling. Based on the results of a meta-analysis in the Gene Expression Profiling Interactive Analysis 2 database, we observed that TSP4 expression levels were consistent with overall survival (OS) rate and BC progression, with the highest expression levels observed in the advanced stages of BC and associated with poor OS rate. In our pilot experiments, incubation with recombinant TSP4 promoted the migration and invasion in BC cells. Furthermore, MMP2 expression levels increased after recombinant TSP4 incubation. TSP4-induced-MMP2 expression and cell motility were regulated via the AKT signalling pathway. Our findings facilitate further investigation into TSP4 silencing-based therapeutic strategies for BC.

Associations With Definitive Outcomes and Clinical Benefit of Cancer Drugs at the Time of Marketing Approval and in the Postmarketing Period.

BACKGROUND: Most anticancer drugs are approved by regulatory agencies based on surrogate measures. This article explores the variables associated with overall survival (OS), quality of life (QoL), and substantial clinical benefit among anticancer drugs at the time of approval and in the postmarketing period. METHODS: Anticancer drugs approved by the FDA between January 2006 and December 2015 and with postmarketing follow-up until April 2019 were identified. We evaluated trial-level data supporting approval and any updated OS and/or QoL data. We applied the ESMO-Magnitude of Clinical Benefit Scale (ESMO-MCBS) and the ASCO Value Framework (ASCO-VF) to initial and follow-up studies. RESULTS: We found that 58 drugs were approved for 96 indications based on 96 trials. At registration, approval was based on improved OS in 39 trials (41%) and improved QoL in 16 of 45 indications (36%). Postmarketing data showed an improvement in OS for 28 of 59 trials (47%) and in QoL for 22 of 48 indications (46%). At the time of approval, 25 of 94 (27%) and 26 of 80 scorable trials (33%) met substantial benefit thresholds using the ESMO-MCBS and ASCO-VF, respectively. In the postmarketing period, 37 of 69 (54%) and 35 of 65 (54%) trials met the substantial benefit thresholds. Drugs with companion diagnostics and immune checkpoint inhibitors were associated significantly with substantial clinical benefit. CONCLUSIONS: Compared with the time of approval, more anticancer drugs showed improved OS and QoL and met the ESMO-MCBS or ASCO-VF thresholds for substantial benefit over the course of postmarketing time. However, only approximately half of the trials met the threshold for substantial benefit. Companion diagnostic drugs and immunotherapy seemed to be associated with greater clinical benefit.

Attenuation of chloroquine and hydroxychloroquine on the invasive potential of bladder cancer through targeting matrix metalloproteinase 2 expression.

Bladder cancer (BC), one of the most common urological neoplastic disorders in men, has an extremely low survival rate because of its tendency to metastasize. The anticancer drugs chloroquine (CQ) and hydroxy CQ (HCQ) might inhibit tumor progression and invasiveness. However, the mechanism by which CQ and HCQ influence BC is undetermined. In this study, CQ and HCQ treatments inhibited the migration and invasion of two BC cell types (5637 and T24) through expression modulation of matrix metalloproteinase-2 (MMP-2), which belongs to the matrix MMP family and is a key mediator of cancer progression. Moreover, additional data revealed that the migrative and invasive effects of BC cells treated with CQ or HCQ were abolished after treatment with rapamycin, which induces autophagy, demonstrating that CQ and HCQ functions in BC are based on autophagy inhibition. In conclusion, our research demonstrated that CQ and HCQ regulated cell motility in BC through MMP-2 downregulation by targeting autophagy functions, providing a novel therapeutic strategy for BC treatment.

Miconazole induces protective autophagy in bladder cancer cells.

Autophagy plays a dual function in cancer progression; autophagy activation can support cancer cell survival or contribute to cell death. Miconazole, a Food and Drug Administration-approved antifungal drug, has been implicated in oncology research recently. Miconazole was found to exert antitumor effects in various tumors, including bladder cancer (BC). However, whether it provokes protective autophagy has been never discussed. We provide evidence that miconazole induces protective autophagy in BC for the first time. The results indicated that 1A/1B-light chain 3 (LC3)-II processing and p62 expression were elevated after miconazole exposure. Also, adenosine monophosphate-activated protein kinase phosphorylation was increased after miconazole treatment. We also confirmed the autophagy-promoting effect of miconazole in the presence of bafilomycin A1 (Baf A1). The result indicates that a combination treatment of miconazole and Baf A1 improved LC3-II processing, confirming that miconazole promoted autophagic flux. The acridine orange, Lysotracker, and cathepsin D staining results indicate that miconazole increased lysosome formation, revealing its autophagy-promoting function. Finally, miconazole and autophagy inhibitor 3-methyladenine cotreatment further reduced the cell viability and induced apoptosis in BC cells, proving that miconazole provokes protective autophagy in BC cells. Our findings approve that miconazole has an antitumor effect in promoting cell apoptosis; however, its function of protective autophagy is needed to be concerned in cancer treatment.

Prices and clinical benefit of cancer drugs in the USA and Europe: a cost-benefit analysis.

BACKGROUND: Increasing cancer drug prices are a challenge for patients and health systems in the USA and Europe. By contrast with the USA, national authorities in European countries often directly negotiate drug prices with manufacturers. The American Society of Clinical Oncology (ASCO) and the European Society for Medical Oncology (ESMO) developed frameworks to evaluate the clinical value of cancer therapies: the ASCO-Value Framework (ASCO-VF) and the ESMO-Magnitude of Clinical Benefit Scale (ESMO-MCBS). We aimed to assess the association between the clinical benefit of approved cancer drugs based on these frameworks and their drug prices in the USA and four European countries (England, Switzerland, Germany, and France). METHODS: For this cost-benefit analysis, we identified all new drugs with initial indications for adult cancers that were approved by the US Food and Drug Administration between Jan 1, 2009, and Dec 31, 2017, and by the European Medicines Agency up until Sept 1, 2019. For drugs indicated for solid tumours, we assessed clinical benefit using ASCO-VF and ESMO-MCBS. We compared monthly drug treatment costs between benefit levels using hierarchical linear regression models, and calculated Spearman's correlation coefficients between costs and benefit levels for individual countries. FINDINGS: Our cohort included 65 drugs: 47 (72%) drugs were approved for solid tumours and 18 (28%) were approved for haematological malignancies. The monthly drug treatment costs in the USA were a median of 2·31 times (IQR 1·79-3·17) as high as in the assessed European countries. There were no significant associations between monthly treatment costs for solid tumours and clinical benefit in all assessed countries, using the ESMO-MCBS (p=0·16 for the USA, p=0·98 for England, p=0·54 for Switzerland, p=0·52 for Germany, and p=0·40 for France), and for all assessed countries except France using ASCO-VF (p=0·56 for the USA, p=0·47 for England, p=0·26 for Switzerland, p=0·23 for Germany, and p=0·037 for France). INTERPRETATION: Cancer drugs with low or uncertain clinical benefit might be prioritised for price negotiations. Value frameworks could help identify therapies providing high clinical benefit that should be made rapidly available across countries. FUNDING: Swiss Cancer Research Foundation (Krebsforschung Schweiz).

Clinical benefit and cost of breakthrough cancer drugs approved by the US Food and Drug Administration.

BACKGROUND: The clinical benefit and pricing of breakthrough-designated cancer drugs are uncertain. This study compares the magnitude of the clinical benefit and monthly price of new and supplemental breakthrough-designated and non-breakthrough-designated cancer drug approvals. METHODS: A cross-sectional cohort comprised approvals of cancer drugs for solid tumors from July 2012 to December 2017. For each indication, the clinical benefit from the pivotal trials was scored via validated frameworks: the American Society of Clinical Oncology Value Framework (ASCO-VF), the American Society of Clinical Oncology Cancer Research Committee (ASCO-CRC), the European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS), and the National Comprehensive Cancer Network (NCCN) Evidence Blocks. A high clinical benefit was defined as scores ≥ 45 for the ASCO-VF, overall survival gains ≥ 2.5 months or progression-free survival gains ≥ 3 months for all cancer types for the ASCO-CRC criteria, a grade of A or B for trials of curative intent and a grade of 4 or 5 for trials of noncurative intent for the ESMO-MCBS, and scores of 4 and 5 and a combined score ≥ 16 for the NCCN Evidence Blocks. Monthly Medicare drug prices were calculated with Medicare prices and DrugAbacus. RESULTS: This study identified 106 trials supporting approval of 52 drugs for 96 indications. Forty percent of these indications received the breakthrough designation. Among the included trials, 33 (43%), 46 (73%), 35 (34%), and 67 (69%) met the thresholds established by the ASCO-VF, ASCO-CRC, ESMO-MCBS, and NCCN, respectively. In the metastatic setting, there were higher odds of clinically meaningful grades in trials supporting breakthrough drugs with the ASCO-VF (odds ratio [OR], 3.69; P = .022) and the NCCN Evidence Blocks (OR, 5.80; P = .003) but not with the ASCO-CRC (OR, 3.54; P = .11) or version 1.1 (v1.1) of the ESMO-MCBS (OR, 1.22; P = .70). The median costs of breakthrough therapy drugs were significantly higher than those of nonbreakthrough therapies (P = .001). CONCLUSIONS: In advanced solid cancers, drugs that received the breakthrough therapy designation were more likely than nonbreakthrough therapy drugs to be scored as providing a high clinical benefit with the ASCO-VF and the NCCN Evidence Blocks but not with the ESMO-MCBS v1.1 or the ASCO-CRC scale.

DETECTION OF CLINICALLY UNSUSPECTED RETINAL NEOVASCULARIZATION WITH WIDE-FIELD OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY.

PURPOSE: To evaluate wide-field optical coherence tomography angiography (OCTA) for detection of clinically unsuspected neovascularization (NV) in diabetic retinopathy (DR). METHODS: This prospective observational single-center study included adult patients with a clinical diagnosis of nonproliferative DR. Participants underwent a clinical examination, standard 7-field color photography, and OCTA with commercial and prototype swept-source devices. The wide-field OCTA was achieved by montaging five 6 × 10-mm scans from a prototype device into a 25 × 10-mm image and three 6 × 6-mm scans from a commercial device into a 15 × 6-mm image. A masked grader determined the retinopathy severity from color photographs. Two trained readers examined conventional and wide-field OCTA images for the presence of NV. RESULTS: Of 27 participants, photographic grading found 13 mild, 7 moderate, and 7 severe nonproliferative DR. Conventional 6 × 6-mm OCTA detected NV in 2 eyes (7%) and none with 3 × 3-mm scans. Both prototype and commercial wide-field OCTA detected NV in two additional eyes. The mean area of NV was 0.38 mm (range 0.17-0.54 mm). All eyes with OCTA-detected NV were photographically graded as severe nonproliferative DR. CONCLUSION: Wide-field OCTA can detect small NV not seen on clinical examination or color photographs and may improve the clinical evaluation of DR.

Benzyl isothiocyanate promotes miR-99a expression through ERK/AP-1-dependent pathway in bladder cancer cells.

Benzyl isothiocyanate (BITC), a bioactive natural product present in cruciferous vegetables, has been proved to prevent cancer progression through various mechanisms. In our previous report, we proved that BITC exhibits antitumor effects in bladder cancer by suppressing IGF1R, FGFR3, and mTOR, which is mediated by miR-99a expression. In this study, we identified the signal pathway involved in regulating miR-99a expression after BITC exposure in bladder cancer. Treatment with different BITC concentrations resulted in induction of miR-99a expression in bladder cancer cell lines. Activation of extracellular signal-regulated protein kinase (ERK) and c-jun N-terminal kinase was observed in bladder cancer after BITC treatment for 24 hours. Interestingly, by using a chemical inhibitor of candidate pathways, we found that only the ERK signal pathway is required for miR-99a expression. Furthermore, we evaluated the transcription factor that may contribute to miR-99a expression in response to BITC treatment. The results indicated that c-Jun/AP-1 was activated after BITC treatment. Moreover, we confirmed c-Jun/AP-1 activation through immunofluorescence and the luciferase reporter assay. The results showed that BITC treatment markedly improved nuclear translocation of c-Jun/AP-1 and luciferase activity dose dependently. Finally, pretreatment with the ERK inhibitor U0126 diminished c-Jun phosphorylation and transcriptional activation, suggesting that BITC elicits ERK/c-Jun signal transduction, which is responsible for miR-99a expression in bladder cancer. The present work identifies the mechanism involved in upregulation miR-99a after BITC treatment, which provides an explanation for BITC biological function in our previous work.

Association between progression-free survival and patients' quality of life in cancer clinical trials.

Quality of life outcomes provide essential information for patients and physicians in oncology care. However, the validity of progression-free survival (PFS) as a surrogate for quality of life, and the inclusion and reporting of quality of life endpoints in clinical trials, is unclear. We performed a retrospective study of phase III clinical trials of drugs for advanced or metastatic solid tumors published between 2010 and 2015. Correlation coefficient (r) and area under the ROC curve (AUC) for association between PFS and positive quality of life were evaluated. Of the 352 Phase 3 trials included, 190 (54%) included a quality of life endpoint, of which 23% did not report pre-specified quality of life outcomes; a total of 125,962 patients were enrolled in studies lacking, or not reporting, quality of life outcomes. Among the 147 trials that reported quality of life outcomes, 99 (67%) reported no effect, 38 (26%) reported a positive effect and 10 (7%) reported a negative effect of treatment on patients' global quality of life. The association between PFS and improvement in global quality of life was weak (r = 0.34; AUC = 0.72), as was the association between PFS and improvement in any domain of quality of life. In conclusion, PFS benefit was not strongly correlated with improvements in patients' quality of life, and, despite the palliative intent of treatments in the advanced/metastatic setting, the availability of quality of life data from clinical trials of cancer drugs was poor.

Changes in Electronic Health Record Use Time and Documentation over the Course of a Decade.

PURPOSE: With the current wide adoption of electronic health records (EHRs) by ophthalmologists, there are widespread concerns about the amount of time spent using the EHR. The goal of this study was to examine how the amount of time spent using EHRs as well as related documentation behaviors changed 1 decade after EHR adoption. DESIGN: Single-center cohort study. PARTICIPANTS: Six hundred eighty-five thousand three hundred sixty-one office visits with 70 ophthalmology providers. METHODS: We calculated time spent using the EHR associated with each individual office visit using EHR audit logs and determined chart closure times and progress note length from secondary EHR data. We tracked and modeled how these metrics changed from 2006 to 2016 with linear mixed models. MAIN OUTCOME MEASURES: Minutes spent using the EHR associated with an office visit, chart closure time in hours from the office visit check-in time, and progress note length in characters. RESULTS: Median EHR time per office visit in 2006 was 4.2 minutes (interquartile range [IQR], 3.5 minutes), and increased to 6.4 minutes (IQR, 4.5 minutes) in 2016. Median chart closure time was 2.8 hours (IQR, 21.3 hours) in 2006 and decreased to 2.3 hours (IQR, 18.5 hours) in 2016. In 2006, median note length was 1530 characters (IQR, 1435 characters) and increased to 3838 characters (IQR, 2668.3 characters) in 2016. Linear mixed models found EHR time per office visit was 31.9±0.2% (P < 0.001) greater from 2014 through 2016 than from 2006 through 2010, chart closure time was 6.7±0.3 hours (P < 0.001) shorter from 2014 through 2016 versus 2006 through 2010, and note length was 1807.4±6.5 characters (P < 0.001) longer from 2014 through 2016 versus 2006 through 2010. CONCLUSIONS: After 1 decade of use, providers spend more time using the EHR for an office visit, generate longer notes, and close the chart faster. These changes are likely to represent increased time and documentation pressure for providers. Electronic health record redesign and new documentation regulations may help to address these issues.

Medicare Incentive Payments to United States Ophthalmologists for Use of Electronic Health Records: 2011-2016.

PURPOSE: To investigate ophthalmologists' rate of attestation to meaningful use (MU) of their electronic health record (EHR) systems in the Medicare EHR Incentive Program and their continuity and success in receiving payments in comparison with other specialties. DESIGN: Administrative database study. PARTICIPANTS: Eligible professionals participating in the Medicare EHR Incentive Program. METHODS: Based on publicly available data sources, subsets of payment and attestation data were created for ophthalmologists and for other specialties. The number of eligible professionals attesting was determined using the attestation data for each year and stage of the program. The proportion of attestations by EHR vendor was calculated using all attestations for each vendor. MAIN OUTCOME MEASURES: Numbers of ophthalmologists attesting by year and stage of the Medicare EHR Incentive Program, incentive payments, and number of attestations by EHR vendor. RESULTS: In the peak year of participation, 51.6% of ophthalmologists successfully attested to MU, compared with 37.1% of optometrists, 50.2% of dermatologists, 54.5% of otolaryngologists, and 64.4% of urologists. Across the 6 years of the program, ophthalmologists received an average of $17 942 in incentive payments compared with $11 105 for optometrists, $16 617 for dermatologists, $20 203 for otolaryngologists, and $23 821 for urologists. Epic and Nextgen were the most frequently used EHRs for attestation by ophthalmologists. CONCLUSIONS: Ophthalmology as a specialty performed better than optometry and dermatology, but worse than otolaryngology and urology, in terms of the proportion of eligible professionals attesting to MU of EHRs. Ophthalmologists were more likely to remain in the program after their initial year of attestation compared with all eligible providers. The top 4 EHR vendors accounted for 50% of attestations by ophthalmologists.

Programmed Cell Death 1 (PD-1) Inhibitors in Renal Transplant Patients with Advanced Cancer: A Double-Edged Sword?

Given advancements in cancer immunity, cancer treatment has gained breakthrough developments. Immune checkpoint inhibitors, such as programmed cell death 1 (PD-1) inhibitors, are the most promising drugs in the field and have been approved to treat various types of cancer, such as metastatic melanoma, head and neck squamous cell carcinoma, and urothelial carcinoma. However, whether PD-1 inhibitors should be administered to renal transplant patients with advanced cancer remains unclear because the T-cells produced after administration of these inhibitors act against not only tumor antigens but also donor alloantigens. Thus, the use of PD-1 inhibitors in kidney-transplanted patients with advanced cancer is limited on account of the high risk of graft failure due to acute rejection. Hence, finding optimal treatment regimens to enhance the tumor-specific T-cell response and decrease T-cell-mediated alloreactivity after administration of a PD-1 inhibitor is necessary. Thus far, no recommendations for the use of PD-1 inhibitors to treat cancer in renal transplant patients are yet available, and very few cases reporting kidney-transplanted patients treated with PD-1 inhibitors are available in the literature. Therefore, in this work, we review the published cases and suggest feasible approaches for renal transplant patients with advanced malignancy treated by a PD-1 inhibitor. Of the 22 cases we obtained, four patients maintained intact grafts without tumor progression after treatment with a PD-1 inhibitor. Among these patients, one maintained steroid dose before initiation of anti-PD1, two received immunosuppressive regimens with low-dose steroid and calcineurin inhibitor (CNI)-elimination with sirolimus before initiation of anti-PD-1 therapy, and one received combined anti-PD-1, anti-vascular endothelial growth factor (VEGF), and chemotherapy with unchanged immunosuppressive regimens. mammalian target of rapamycin (mTOR) inhibitors and anti-VEGF may act as regulators of tumor-specific and allogenic T-cells. However, more studies are necessary to explore the optimal therapy and ensure the safety and efficacy of PD-1 inhibitors in kidney-transplanted patients.

Delays in completion and results reporting of clinical trials under the Paediatric Regulation in the European Union: A cohort study.

BACKGROUND: Few medicines have been approved for children, leading to rates of off-label prescribing reported to be as high as 90%. In 2007, the European Union adopted the Paediatric Regulation, which mandates that pharmaceutical companies conduct paediatric studies for all new medicines, unless granted a waiver. We aimed to evaluate the availability of paediatric trial results from studies required under the Paediatric Regulation for new medicines authorised in the EU. METHODS AND FINDINGS: The European Medicines Agency (EMA) public database of paediatric investigation plans was searched for new medicines centrally authorised in the EU between 1 January 2010 and 31 December 2014 with at least 1 required paediatric study. For our study cohort of paediatric clinical trials required for these medicines, we used internal EMA databases and publicly available trial registries to determine changes to the planned completion date or study design, rates of trial completion, time to trial completion, and results reporting (peer-reviewed publication or posting on trial registry). Cox proportional hazards regression models were constructed to examine factors associated with study completion. A total of 326 paediatric clinical trials were required for 122 novel medicines authorised by the EMA between 2010 and 2014. In all, 76% (247/326) of paediatric studies were not planned to be completed until after the initial marketing authorisation. The planned completion dates for 50% (162/326) were further postponed by a median of 2.2 years. Overall, 38% (124/326) of paediatric studies were completed as of 30 November 2017. The rate of trial completion for paediatric studies planned to be completed after initial marketing authorisation was 23% (56/247), versus 86% (68/79) for trials planned to be completed before authorisation (adjusted hazard ratio 0.11; 95% CI 0.06-0.19). Among completed studies, the results were reported in a public registry or in the peer-reviewed literature for 85% (105/124) at a median of 1.1 years after study completion, and 60% (74/124) were published in a peer-reviewed journal. Limitations of this study include the potential lack of generalisability to medicines not authorised by the EMA and the possibility for more of these trials to be completed or published in the future. CONCLUSIONS: The completion of many paediatric studies required under the Paediatric Regulation has been delayed. Paediatric studies planned to be completed after marketing authorisation were associated with a lower likelihood of eventual completion, highlighting the need to examine the implementation of current policies in ensuring timely availability of important paediatric information.