Somatic MED12 Mutations in Myometrial Cells.

Over 70% of leiomyoma (LM) harbor MED12 mutations, primarily in exon 2 at c.130-131 (GG). Myometrial cells are the cell origin of leiomyoma, but the MED12 mutation status in non-neoplastic myometrial cells is unknown. In this study, we investigated the mutation burden of MED12 in myometrium. As traditional Sanger or even NGS sequencing may not be able to detect MED12 mutations that are lower than 0.1% in the testing sample, we used duplex deep sequencing analysis (DDS) to overcome this limitation. Tumor-free myometria (confirmed by pathology evaluation) were dissected, and genomic DNA from MED12 exon 2 (test) and TP53 exon 5 (control) were captured by customer-designed probe sets, followed by DDS. Notably, DDS demonstrated that myometrial cells harbored a high frequency of mutations in MED12 exon 2 and predominantly in code c.130-131. In contrast, the baseline mutations in other coding sequences of MED12 exon 2 as well as in the TP53 mutation hotspot, c.477-488 were comparably low in myometrial cells. This is the first report demonstrating a non-random accumulation of MED12 mutations at c.130-131 sites in non-neoplastic myometrial cells which provide molecular evidence of early somatic mutation events in myometrial cells. This early mutation may contribute to the cell origin for uterine LM development in women of reproductive age.

Primary Retinal Detachment Repair in Eyes Deemed High Risk for Proliferative Vitreoretinopathy: Surgical Outcomes in 389 Eyes.

PURPOSE: To evaluate surgical outcomes in eyes with primary rhegmatogenous retinal detachment (RRD) deemed at high risk for postoperative proliferative vitreoretinopathy (PVR). DESIGN: Retrospective, consecutive case cohort study. PARTICIPANTS: Eyes undergoing primary RRD repair with pars plana vitrectomy (PPV) or combined PPV with scleral buckling (PPV/SB) between January 1, 2016, and December 30, 2017, at Wills Eye Hospital. METHODS: Eyes were defined as "high risk" if ≥ 1 of the following risk factors for PVR was present on preoperative examination: preoperative PVR grade A or B, vitreous hemorrhage, RRD involving ≥ 50% of retinal area, presence of ≥ 3 retinal breaks, history of prior cryotherapy, presence of choroidal detachment, or duration of RRD > 2 weeks. Surgical failure was defined as an additional intervention required for the retinal reattachment. MAIN OUTCOMES MEASURES: Single surgery attachment success (SSAS) rate 3 months after first surgical intervention for primary RRD. RESULTS: Of 2053 reviewed charts, a total of 389 eyes (18.9%) met the definition of high risk and were included in the analysis. Mean patient age was 63.5 years. PPV/SB was performed in 125 (32.1%) eyes and PPV alone in 264 (67.9%) eyes. SSAS rate of the overall cohort was 71.5% at 3 months. SSAS rate was significantly higher in eyes treated with PPV/SB compared with PPV (80.8% vs. 67%, respectively, P = 0.006). On multivariate analysis, use of PPV/SB was the only feature associated with SSAS (odds ratio, 2.04; 95% confidence interval, 1.12-3.69, P = 0.019). CONCLUSION: In eyes with primary RRD and risk factors for PVR, overall SSAS was 71.5% after primary repair. In this cohort, use of PPV/SB was associated with a significantly higher SSAS compared with PPV alone. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Artificial Intelligence-Driven Morphology-Based Enrichment of Malignant Cells from Body Fluid.

Cell morphology is a fundamental feature used to evaluate patient specimens in pathologic analysis. However, traditional cytopathology analysis of patient effusion samples is limited by low tumor cell abundance coupled with the high background of nonmalignant cells, restricting the ability of downstream molecular and functional analyses to identify actionable therapeutic targets. We applied the Deepcell platform that combines microfluidic sorting, brightfield imaging, and real-time deep learning interpretations based on multidimensional morphology to enrich carcinoma cells from malignant effusions without cell staining or labels. Carcinoma cell enrichment was validated with whole genome sequencing and targeted mutation analysis, which showed a higher sensitivity for detection of tumor fractions and critical somatic variant mutations that were initially at low levels or undetectable in presort patient samples. Our study demonstrates the feasibility and added value of supplementing traditional morphology-based cytology with deep learning, multidimensional morphology analysis, and microfluidic sorting.

PRAME expression by immunohistochemistry and reverse transcription quantitative PCR in conjunctival melanocytic lesions-a comprehensive clinicopathologic study of 202 cases and correlation of cytogenetics with PRAME expression in challenging conjunctival melanocytic lesions.

This study examined PRAME (preferentially expressed antigen in melanoma) expression by immunohistochemistry and reverse transcription quantitative PCR (RT-qPCR) in 202 histologically unequivocal conjunctival melanocytic lesions: 76 nevi, 29 benign melanoses, 25 low-grade conjunctival intraepithelial melanocytic lesions (LGCMIL), 26 high-grade conjunctival melanocytic intraepithelial lesions/in-situ melanoma (HGCMIL), and 46 invasive melanomas. PRAME score 0 was seen in 96% of nevi (73/76), 96% of benign melanoses (28/29), and 88% of LGCMIL (22/25). PRAME score 4 was seen in 50% HGCMIL (13/26) and 76% invasive melanomas (35/46). PRAME score 4 had a sensitivity of 50% and specificity of 100% in differentiating between HGCMIL and benign melanosis/LGCMIL. PRAME score 4 had a sensitivity of 76% and specificity of 100% in differentiating between melanoma and nevi. Relative quantification of PRAME mRNA expression by RT-qPCR was performed on 49 cases (24%): 17 nevi, 3 benign melanoses, 5 LGCMIL, 9 HGCMIL, and 15 invasive melanomas. The analysis generated two distinct groupings with 'high' relative PRAME expression for the HGCMIL and invasive melanoma and 'low/zero' expression for nevi, benign melanosis, and LGCMIL. Thirty-three challenging conjunctival melanocytic lesions that had previous fluorescence in situ hybridization (FISH) analysis were studied: 18 nevi, 12 melanomas in a nevus, 2 nevoid melanomas, and 1 in-situ melanoma. All nevi (100%) showed concordance between negative FISH and PRAME (scores 0-3). Four of 13 melanomas (31%; in-situ, invasive, isolated, and in association with nevus) showed concordance between positive FISH and PRAME score 4. In conclusion, PRAME score 4 has 100% specificity for the diagnosis of HGCMIL and melanoma. PRAME is limited in its sensitivity in the evaluation of challenging melanocytic lesions.

NANOG regulates epithelial-mesenchymal transition via AMPK/mTOR signalling pathway in ovarian cancer SKOV-3 and A2780 cells.

NANOG engages with tumour initiation and metastasis by regulating the epithelial-mesenchymal transition (EMT) in epithelial ovarian cancer (EOC). However, its role in association with pAMPKα, and its clinical significance in EOC have not been elucidated even though AMPK is known to degrade NANOG in various human cancers. Hence, we investigated the role of pAMPKα and its association with NANOG as potential prognostic biomarkers in EOC. Both NANOG and pAMPKα expression were significantly overexpressed in EOCs comparing nonadjacent normal epithelial tissues, benign tissues, and borderline tumours. NANOG overexpression was significantly associated with poor disease-free survival (DFS) and overall survival (OS), whereas pAMPKα overexpression was associated with good DFS and OS. Importantly, multivariate analysis revealed that the combination of high NANOG and low pAMPKα expression was a poor independent prognostic factor for DFS and was associated with platinum resistance. In ovarian cancer cell lines, siRNA-mediated NANOG knockdown diminished migration and invasion properties by regulating the EMT process via the AMPK/mTOR signalling pathway. Furthermore, treatment with AMPK activator suppressed expression of stemness factors such as NANOG, Oct4 and Sox2. Collectively, these findings established that the combination of high NANOG and low pAMPKα expression was associated with EOC progression and platinum resistance, suggesting a potential prognostic biomarker for clinical management in EOC patients.

RNA sequencing and bioinformatics analysis revealed PACSIN3 as a potential novel biomarker for platinum resistance in epithelial ovarian cancer.

BACKGROUND: Failure to respond to treatment in epithelial ovarian cancer can often be attributed to platinum-based chemotherapy resistance. However, the possible mechanisms or candidate biomarkers associated with platinum resistance are yet to be elucidated, even though many researchers have performed related studies. METHODS: We performed RNA sequencing of clinical specimens obtained from patients with platinum-sensitive or resistant epithelial ovarian cancer (EOC). Furthermore, various bioinformatics approaches, including spatial analysis of functional enrichment, were used to identify key regulators and associated underlying mechanisms of platinum resistance in EOC. RESULTS: Through RNA-sequencing, we identified 263 differentially expressed genes (98 upregulated and 165 downregulated) and subjected them to Gene Oncology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses, which were characterized to the traditional platinum-resistant characteristics. Subsequently, the gene interaction network and module analysis by spatial analysis of functional enrichment software demonstrated protein kinase C and casein kinase substrate in neurons 3 (PACSIN3) as the only upregulated hub gene, and neurotensin (NTS) and KIAA0319 as downregulated hub genes in platinum-resistant EOC. We selected PACSIN3 for further analysis because it has not been studied in relation to response to platinum-based chemotherapy. PACSIN3 was significantly upregulated in ovarian cancer cells compared to immortalized human ovarian surface epithelial cells. In addition, cisplatin-induced apoptosis was measured in PACSIN3 knockout OVCA433 and BRCA-mutated EOC cell line, SNU251, by a fluorescence-activated cell sorting-based Annexin-V/propium iodide double staining assay, which revealed a significant increase in apoptosis. CONCLUSIONS: Taken together, the present study presents PACSIN3 as a promising predictive biomarker associated with platinum resistance, especially in BRCA-mutated epithelial ovarian cancers.

Overexpression of glucocorticoid receptor promotes the poor progression and induces cisplatin resistance through p38 MAP kinase in cervical cancer patients.

Glucocorticoid receptor (GR) is activated by synthetic glucocorticoid or endogenous cortisol which were released by the physical and psychosocial stress, and recent studies reported that it is involved in tumor initiation and metastasis in various solid cancers. However, role of GR in cervical cancer has not been elucidated yet. Therefore, here we aim to unveil the role of GR in cervical cancer with cervical cancer clinical specimen and cervical cancer cell lines. We found that overexpression of GR was associated with poor prognosis in cervical cancer patients. Also, GR knockdown in cervical cancer cell lines showed diminished proliferation, invasion and EMT properties. Besides, we found that GR was positively associated with FoxP3 expression, and combination of GR and FoxP3 overexpression revealed as more reliable biomarker for poor prognosis and poor response to chemotherapy of cervical cancer patient than GR alone. Moreover, FACS-based Annexin-V/PI double staining and cleavage of poly ADP ribose polymerase (PARP) showed that siGR enhanced cisplatin-induced apoptosis, which was mediated by p38 MAP kinase. Collectively, our findings established that the combination of high GR and FoxP3 was associated with cervical cancer progression and platinum resistance, suggesting a potential predictive biomarker for clinical management in patients with cervical cancer.

Factors Associated with Increased Risk for Pulmonary Embolism After Metabolic and Bariatric Surgery: Analysis of Nearly One Million Patients.

BACKGROUND: Metabolic and bariatric surgery (MBS) has a low incidence of post-operative morbidity and mortality. Understanding risk factors associated with complications that occur allows surgeons to define at-risk patients and assess the need for preventive and prophylactic measures. OBJECTIVES: To determine risk factors associated with development of pulmonary embolism (PE) within 30 days of MBS and to predict the increased risk for mortality when PE occurs. SETTING: USA, MBSAQIP database. METHODS: Analysis of the MBSAQIP database was undertaken. This included information on 966,646 MBS cases from 2015 to 2019 in the USA. RESULTS: Twenty-two risk factors for development of PE post-MBS were identified to be statistically significant. CONCLUSIONS: PE is a relatively uncommon complication after MBS. When it does occur, there is a 50.9-fold increased risk for mortality. Patients with significant risk factors for PE may benefit from higher dose perioperative and/or extended VTE prophylaxis after MBS.

Global Level Quantification of Histone Post-Translational Modifications in a 3D Cell Culture Model of Hepatic Tissue.

Flat cultures of mammalian cells are a widely used in vitro approach for understanding cell physiology, but this system is limited in modeling solid tissues due to unnaturally rapid cell replication. This is particularly challenging when modeling mature chromatin, as fast replicating cells are frequently involved in DNA replication and have a heterogeneous polyploid population. Presented below is a workflow for modeling, treating, and analyzing quiescent chromatin modifications using a three-dimensional (3D) cell culture system. Using this protocol, hepatocellular carcinoma cell lines are grown as reproducible 3D spheroids in an incubator providing active nutrient diffusion and low shearing forces. Treatment with sodium butyrate and sodium succinate induced an increase in histone acetylation and succinylation, respectively. Increases in levels of histone acetylation and succinylation are associated with a more open chromatin state. Spheroids are then collected for isolation of cell nuclei, from which histone proteins are extracted for the analysis of their post-translational modifications. Histone analysis is performed via liquid chromatography coupled online with tandem mass spectrometry, followed by an in-house computational pipeline. Finally, examples of data representation to investigate the frequency and occurrence of combinatorial histone marks are shown.

Semisupervised Training of a Brain MRI Tumor Detection Model Using Mined Annotations.

Background Artificial intelligence (AI) applications for cancer imaging conceptually begin with automated tumor detection, which can provide the foundation for downstream AI tasks. However, supervised training requires many image annotations, and performing dedicated post hoc image labeling is burdensome and costly. Purpose To investigate whether clinically generated image annotations can be data mined from the picture archiving and communication system (PACS), automatically curated, and used for semisupervised training of a brain MRI tumor detection model. Materials and Methods In this retrospective study, the cancer center PACS was mined for brain MRI scans acquired between January 2012 and December 2017 and included all annotated axial T1 postcontrast images. Line annotations were converted to boxes, excluding boxes shorter than 1 cm or longer than 7 cm. The resulting boxes were used for supervised training of object detection models using RetinaNet and Mask region-based convolutional neural network (R-CNN) architectures. The best-performing model trained from the mined data set was used to detect unannotated tumors on training images themselves (self-labeling), automatically correcting many of the missing labels. After self-labeling, new models were trained using this expanded data set. Models were scored for precision, recall, and F1 using a held-out test data set comprising 754 manually labeled images from 100 patients (403 intra-axial and 56 extra-axial enhancing tumors). Model F1 scores were compared using bootstrap resampling. Results The PACS query extracted 31 150 line annotations, yielding 11 880 boxes that met inclusion criteria. This mined data set was used to train models, yielding F1 scores of 0.886 for RetinaNet and 0.908 for Mask R-CNN. Self-labeling added 18 562 training boxes, improving model F1 scores to 0.935 (P < .001) and 0.954 (P < .001), respectively. Conclusion The application of semisupervised learning to mined image annotations significantly improved tumor detection performance, achieving an excellent F1 score of 0.954. This development pipeline can be extended for other imaging modalities, repurposing unused data silos to potentially enable automated tumor detection across radiologic modalities. © RSNA, 2022 Online supplemental material is available for this article.

Patient and Provider Satisfaction with Telemedicine in a Comprehensive Weight Management Program.

Introduction: Telemedicine use became widespread at our weight management center in 2020 due to the coronavirus disease 2019 (COVID-19) pandemic. Objectives: The objective of this study was to determine patient and provider satisfaction with telemedicine visits at a community-based hospital in the United States. Methods: Patients and providers were electronically surveyed at the end of 2020 regarding telemedicine visit experiences. These visits took place throughout the majority of 2020 during the COVID-19 pandemic. Results: A total of 85.7% (6) of providers reported spending the same or less time on telemedicine visits compared with in-person visits. All providers were either somewhat or very satisfied with the interpersonal connections made in telemedicine visits. All providers wished to see telemedicine visits continued in the future. A total of 355 patients responded. Over 90% of participants reported feeling comfortable speaking to their provider about personal issues through telemedicine. Around 73.2% of patients were very satisfied with their telemedicine visit. Around 69.8% of patients report that they would like to use either primarily telemedicine visits or a combination of telemedicine and in-person visits when it is safe to return to in-person care. Conclusions: Patients and providers exhibited high levels of satisfaction with telemedicine use in a weight management center. They both wish to see these visit types offered in the future. Patients who saved more than 30 min of time traveling with a telemedicine visit were significantly more likely to show high levels of satisfaction. Patients who found it easier to connect with the virtual platforms also were significantly more likely to have higher satisfaction levels.

CRY1 Regulates Chemoresistance in Association With NANOG by Inhibiting Apoptosis via STAT3 Pathway in Patients With Cervical Cancer.

BACKGROUND/AIM: Cryptochrome 1 (CRY1), a core circadian gene, modulates circadian rhythm and carcinogenesis. Here, we investigated the role of CRY1 and its correlation with NANOG, a stem cell transcription factor, in cervical cancer. MATERIALS AND METHODS: Immunohistochemistry with tissue microarray was performed to evaluate CRY1 and NANOG expression in cervical cancer tissues, and their functional roles were assessed in cervical cancer cell lines. RESULTS: CRY1 or NANOG was significantly over-expressed in cervical cancer tissues. Notably, combined over-expression of CRY1 and NANOG was correlated with a significantly poor OS and DFS and showed a stronger predictive value for chemoradiation response than each single protein. Furthermore, siCRY1 induced apoptosis, decreased NANOG expression, suppressed STAT3 signalling, and activated p53 signalling in cervical cancer cell lines. CONCLUSION: CRY1 and NANOG over-expression serves as a strong predictive biomarker for prognosis and chemoradiation response, and may be a new therapeutic target in patients with cervical cancer.

Predictive Value of the Atherogenic Index of Plasma (AIP) for the Risk of Incident Ischemic Heart Disease among Non-Diabetic Koreans.

The atherogenic index of plasma (AIP), composed of triglycerides and high-density lipoprotein cholesterol, is a novel critical marker for assessing the risk of atherogenicity and cardiometabolic health. We aimed to prospectively study the association between AIP and incident ischemic heart disease (IHD) risk in a large cohort of non-diabetic Korean adults. Data were assessed from 17,944 participants without diabetes from the Health Risk Assessment Study (HERAS) and Korea Health Insurance Review and Assessment (HIRA) data. The participants were divided into four groups according to AIP quartiles, calculated as log (triglyceride/high-density lipoprotein cholesterol). We prospectively assessed hazard ratios (HRs) with 95% confidence intervals (CIs) for IHD using multivariate Cox proportional-hazard regression models over a 50-month period that followed the baseline survey. During the follow-up period, 332 participants (1.9%) developed IHD. HRs of IHD for AIP quartiles 2-4 were 1.58 (95% CI, 1.03-2.43), 1.82 (95% CI, 1.20-2.78), and 2.11 (95% CI, 1.37-3.24) after adjusting for age, sex, body mass index, smoking status, alcohol intake, physical activity, mean arterial blood pressure, fasting plasma glucose, high-sensitivity C-reactive protein level, and hypertension medication. Higher AIP levels may precede and predict the development of IHD in non-diabetic Korean adults.

Bariatric Surgery is Safe for Patients After Recovery from COVID-19.

BACKGROUND: Studies of patients who have undergone surgery while infected with COVID-19 have shown increased risks for adverse outcomes in both pulmonary complications and mortality. It has become clear that the risk of complications from perioperative COVID-19 infection must be weighed against the risk from delayed surgical treatment. Studies have also shown that prior bariatric surgery conveys protection against mortality from COVID-19 and that obesity is the biggest risk factor for mortality from COVID-19 infection in adults under 45 years of age. Studies in patients who have fully recovered from COVID-19 and underwent elective surgery have not become widely available yet. OBJECTIVES: This multi-institutional case series is presented to highlight patients who developed COVID-19, fully recovered, and subsequently underwent elective bariatric surgery with 30-day outcomes available. SETTING: Nine bariatric surgery centers located across the United States. METHODS: This multicenter case series is a retrospective chart review of patients who developed COVID-19, recovered, and subsequently underwent bariatric surgery. Fifty-three patients are included, and 30-day morbidity and mortality were analyzed. RESULTS: Thirty-day complications included esophageal spasm, dehydration, and ileus. There were no cardiovascular, venous thromboembolism (VTE) or respiratory events reported. There were no 30- day mortalities. CONCLUSIONS: Bariatric surgery has been safely performed in patients who made a full recovery from COVID-19 without increased complications due to cardiovascular, pulmonary, venous thromboembolism, or increased mortality rates.

Mode of detection matters: Differences in screen-detected versus symptomatic breast cancers.

OBJECTIVE: Although extensive analyses evaluating screening mammography for breast cancer have been published, some utilized databases do not distinguish between modes of detection, which confounds the conclusions made about the impact of screening mammography. METHODS: A retrospective cohort study of women at our institution with pathologically-proven breast cancer from January 2015 to April 2018 was conducted. Subjects were categorized by their mode of diagnosis: screening or non-screening. Patient demographics, tumor characteristics, and treatments were compared between detection methods using Wilcoxon rank-sum test for continuous variables and chi-squared or Fisher's exact test. RESULTS: 1026 breast cancers were analyzed. 80.8% of screen-detected breast cancers were invasive. Compared to symptomatically detected cancers, screen-detected were smaller (median size 8 mm vs. 15 mm, p < 0.001), less invasive (80.8% vs. 94.3), had a lower pathologic grade (29% grade 3 vs. 45.7%, p < 0.001), a lower clinical stage, and less aggressive histology (51.9% low Ki67 vs. 30.5%, and 88.2% HER2 negative vs. 76.6%, p < 0.001). Screen-detected cancers were less likely to have extramammary disease (13.2% positive lymph nodes vs. 34.0% and 0.4% distant metastases vs. 6.9%, p < 0.001). Women with screen-detected cancers were more likely to undergo conservative treatment (74.8% underwent lumpectomy vs. 59.9%, and 80.0% received no chemotherapy vs. 51.3%, p < 0.001). CONCLUSION: In this study, while the vast majority of screen-detected cancers were invasive, they were more likely to be smaller, less aggressive, and a lower pathologic grade and clinical stage. Furthermore, women with screen-detected cancers were less likely to have extramammary disease and more likely to undergo conservative treatment.

Systemic Immunosuppression and Risk of Endophthalmitis After Intravitreal Anti-Vascular Endothelial Growth Factor Injections.

BACKGROUND AND OBJECTIVE: To evaluate the impact of systemic immunosuppressive therapy on the rates and outcomes of endophthalmitis following intravitreal anti-vascular endothelial growth factor (VEGF) injections. PATIENTS AND METHODS: A retrospective, single-center, comparative cohort study examining eyes undergoing intravitreal anti-VEGF injections from January 2016 to September 2019. Cohorts were created based on concurrent immunosuppressive therapy at time of injection. RESULTS: Of 270,347 anti-VEGF injections administered, 1,300 injections (0.48%) were administered while on systemic immunosuppressive therapy. The odds of endophthalmitis occurring in the immunosuppression group was 9.86 (95% confidence interval [CI], 4.0-24.3; P < .001) times higher than the no-immunosuppression group. Symptom onset occurred 2.51 (95% CI, 0.15-4.870; P = .040) days earlier in the immunosuppression cohort; visual acuity at 6 months after treatment was similar in both groups. CONCLUSIONS: Patients on systemic immunosuppressive medications undergoing intravitreal injections may be at increased risk for post-injection endophthalmitis and may have earlier symptom onset. However, visual outcomes were similar between the two groups. [Ophthalmic Surg Lasers Imaging Retina. 2021;52:S17-S22.].

Breast cancer in women under age 40: A decade of trend analysis at a single institution.

BACKGROUND: Women should be evaluated for breast cancer risk by age 30 to assess for screening need. Recent trends in breast cancer in this population may further inform recommendations. OBJECTIVE: The aim of this study was to analyze trends over time in the rate of breast cancer, tumor characteristics and treatment in women under age 40. METHODS: Retrospective cohort study of women under age 40 at our institution diagnosed with breast cancer from January 2007 to April 2018 was conducted. Patient demographics, tumor characteristics and treatment outcomes were collected. Descriptive statistics and the Mann-Kendell Trend test were calculated. Two-proportion z-tests were used to compare proportions of stage, pathology and treatment between 2007-2013 and 2014-2018. RESULTS: 197 women under age 40 were treated for a new diagnosis of breast cancer at our institution. A higher proportion of women were diagnosed with invasive carcinoma in 2013-2018 (91%) compared to 2007-2012 (78%), p = 0.008. A higher proportion of women were diagnosed with advanced stage disease (stage III-IV) in 2013-2018 (24%) compared to 2007-2012 (2%), p = 0.001. No statistically significant evidence for an increasing trend of overall rate of breast cancer over the last 11 years (p = 0.419) was observed. CONCLUSIONS: While no statistically significant increase in overall rate of breast cancer was noted, an increase in invasive and later staged breast cancers was observed. CLINICAL IMPACT: Rise in more aggressive cancers in a population that is largely not screened may have implications both on the individual young woman's morbidity as well as on a public health level.

Validation of Remote Collection of Patient-Reported Outcomes Using Patients' Smartphones.

BACKGROUD: The purpose of this study was to examine the between-mode equivalence and the relative efficiency of the 2 available modes of patient-reported outcome (PRO) data collection: a web-enabled touch screen tablet and a smartphone in a sample of patients who underwent foot and ankle orthopedic surgery. METHODS: A total of 136 patients who visited the clinic after foot/ankle surgery participated in the study. All patients completed the PRO questionnaire set using tablets at the hospital. After 24 hours of completing the first PRO questionnaire, the patients completed the same PRO questionnaire at home using their personal smartphones. The outcomes were statistically compared, and the patients' preferences were surveyed. RESULTS: The intraclass correlation coefficients for comparing the results of PRO measurements between the 2 modes were 0.970 for the visual analog scale, 0.952 for the Foot Function Index, 0.959 for the foot and ankle outcome scale, and 0.957 for the patient's satisfaction. Sixty-eight participants (58.6%) responded that they were able to answer the questionnaires with more honesty at home using their smartphones. Regarding the mode, 60 participants (48.1%) responded that they have no preference between the devices. CONCLUSIONS: The results of this study showed the equivalence of the 2 modes of PRO data collection: web-enabled touch screen tablets and smartphones. Smartphones may be the preferred mode of PRO measurement, due to their easy accessibility, increased privacy, and the patients' increased honesty in answering questionnaires.

Design of BET Inhibitor Bottlebrush Prodrugs with Superior Efficacy and Devoid of Systemic Toxicities.

Prodrugs engineered for preferential activation in diseased versus normal tissues offer immense potential to improve the therapeutic indexes (TIs) of preclinical and clinical-stage active pharmaceutical ingredients that either cannot be developed otherwise or whose efficacy or tolerability it is highly desirable to improve. Such approaches, however, often suffer from trial-and-error design, precluding predictive synthesis and optimization. Here, using bromodomain and extra-terminal (BET) protein inhibitors (BETi)-a class of epigenetic regulators with proven anticancer potential but clinical development hindered in large part by narrow TIs-we introduce a macromolecular prodrug platform that overcomes these challenges. Through tuning of traceless linkers appended to a "bottlebrush prodrug" scaffold, we demonstrate correlation of in vitro prodrug activation kinetics with in vivo tumor pharmacokinetics, enabling the predictive design of novel BETi prodrugs with enhanced antitumor efficacies and devoid of dose-limiting toxicities in a syngeneic triple-negative breast cancer murine model. This work may have immediate clinical implications, introducing a platform for predictive prodrug design and potentially overcoming hurdles in drug development.