Distinct and combinatorial functions of Jmjd2b/Kdm4b and Jmjd2c/Kdm4c in mouse embryonic stem cell identity.

Self-renewal and pluripotency of embryonic stem cells (ESCs) are established by multiple regulatory pathways operating at several levels. The roles of histone demethylases (HDMs) in these programs are incompletely defined. We conducted a functional RNAi screen for HDMs and identified five potential HDMs essential for mouse ESC identity. In-depth analyses demonstrate that the closely related HDMs Jmjd2b and Jmjd2c are necessary for self-renewal of ESCs and induced pluripotent stem cell generation. Genome-wide occupancy studies reveal that Jmjd2b unique, Jmjd2c unique, and Jmjd2b-Jmjd2c common target sites belong to functionally separable Core, Polycomb repressive complex (PRC), and Myc regulatory modules, respectively. Jmjd2b and Nanog act through an interconnected regulatory loop, whereas Jmjd2c assists PRC2 in transcriptional repression. Thus, two HDMs of the same subclass exhibit distinct and combinatorial functions in control of the ESC state. Such complexity of HDM function reveals an aspect of multilayered transcriptional control.

Neoadjuvant Yttrium-90 Transarterial Radioembolization with Resin Microspheres Prescribed Using the Medical Internal Radiation Dose Model for Intrahepatic Cholangiocarcinoma.

PURPOSE: To evaluate outcomes of patients with intrahepatic cholangiocarcinoma (iCCA) undergoing neoadjuvant yttrium-90 (90Y) transarterial radioembolization (TARE) with resin microspheres prescribed using the Medical Internal Radiation Dose (MIRD) model. MATERIALS AND METHODS: This retrospective institutional review board-approved study included 37 patients with iCCA treated with 90Y-TARE from October 2015 to September 2020. The primary outcome was overall survival (OS) from 90Y-TARE. The secondary outcomes were progression-free survival (PFS), Response Evaluation Criteria In Solid Tumors 1.1 imaging response, and downstaging to resection. Patients with tumor proximity to the middle hepatic vein (<1 cm) and/or insufficient future liver remnant were treated with neoadjuvant intent (n = 21). Patients were censored at the time of surgery or at the last follow-up for the Kaplan-Meier survival analysis. RESULTS: For 31 patients (69 years; interquartile range, 64-74 years; 20 men [65%]) included in the study, the first-line therapy was 90Y-TARE for 23 (74%) patients. Imaging assessment at 6 months showed a disease control rate of 86%. The median PFS was 5.4 months (95% confidence interval [CI], 3-not reached). The PFS was higher after first-line 90Y-TARE (7.4 months [95% CI, 5.3-not reached]) than that after subsequent 90Y-TARE (2.7 months [95% CI, 2-not reached]) (P = .007). The median OS was 22 months (95% CI, 7.3-not reached). The 1- and 2-year OS rates were 60% (95% CI, 41%-86%) and 40% (95% CI, 19.5%-81%). In patients treated with neoadjuvant intent, 11 of 21 patients (52%) underwent resections. The resection margins were R0 and R1 in 8 (73%) and 3 (27%) of 11 patients, respectively. On histological review in 10 patients, necrosis of ≥90% tumor was achieved in 7 of 10 patients (70%). CONCLUSIONS: First-line 90Y-TARE prescribed using the MIRD model as neoadjuvant therapy for iCCA results in good survival outcome and R0 resection for unresectable patients.

Prospective Evaluation of the Cost of Performing Breast Imaging Examinations Using a Time-Driven Activity-Based Costing Method: A Single-Center Study.

OBJECTIVE: Measuring the cost of performing breast imaging is difficult in healthcare systems. The purpose of our study was to evaluate this cost using time-driven activity-based costing (TDABC) and to evaluate cost drivers for different exams. METHODS: An IRB-approved, single-center prospective study was performed on 80 female patients presenting for breast screening, diagnostic or biopsy exams from July 2020 to April 2021. Using TDABC, data were collected for each exam type. Included were full-field digital mammography (FFDM), digital breast tomosynthesis (DBT), contrast-enhanced mammography (CEM), US and MRI exams, and stereotactic, US-guided and MRI-guided biopsies. For each exam type, mean cost and relative contributions of equipment, personnel and supplies were calculated. RESULTS: Screening MRI, CEM, US, DBT, and FFDM costs were $249, $120, $83, $28, and $30. Personnel was the major contributor to cost (60.0%-87.0%) for all screening exams except MRI where equipment was the major contributor (62.2%). Diagnostic MRI, CEM, US, and FFDM costs were $241, $123, $70, and $43. Personnel was the major contributor to cost (60.5%-88.6%) for all diagnostic exams except MRI where equipment was the major contributor (61.8%). Costs of MRI-guided, stereotactic and US-guided biopsy were $1611, $826, and $356. Supplies contributed 40.5%-49.8% and personnel contributed 30.7%-55.6% to the total cost of biopsies. CONCLUSION: TDABC provides assessment of actual costs of performing breast imaging. Costs and contributors varied across screening, diagnostic and biopsy exams and modalities. Practices may consider this methodology in understanding costs and making changes directed at cost savings.

Time-Driven Activity-Based Costing in Interventional Oncology: Cost Measurement and Cost Variability for Hepatocellular Carcinoma Therapies.

PURPOSE: To use time-drive activity-based costing (TDABC) to characterize and compare costs of transarterial chemoembolization (TACE), transarterial radioembolization (TARE), and ablation. METHODS: This three-part study involved (1) prospective observation to record resources used during TACE, TARE, and ablation and statistical evaluation of interobserver and interprocedure variability; (2) Bland-Altman analysis of prospective measurements and medical record time stamps to establish practicality of using retrospective data in place of direct observation; (3) retrospective time stamp assessment for 117 ablations, 61 TACE procedures, and 61 TARE procedures to reveal variability drivers. RESULTS: Ablation costs were lowest ($3,744), which were 74% of TACE costs ($5,089) and 18% of TARE costs ($20,818). Consumables were the greatest cost contributor, accounting for 65% of ablation, 58% of TACE, and 90% of TARE costs. A single consumable contributed to most of the overall costs: the ablation probe (42%), ethiodized oil for TACE (30%), and yttrium-90 microspheres for TARE (80%). Bland-Altman analysis showed agreement between retrospective time stamps and prospective measurements. Ablation costs increased from $3,288 to $4,245 to $4,461 for one, two, or three tumors treated. TACE cost increased from $5,051 to $5,296 for lobar versus selective approaches. CONCLUSION: A bottom-up costing approach using TDABC is feasible to assess true costs of hepatocellular carcinoma treatments and demonstrates ablation costs are significantly less than those of TACE and TARE. Replication of these methods at other institutions can facilitate development of a bundled payment model to promote utilization of locoregional therapies for hepatocellular carcinoma.

Extrahepatic transarterial radioembolization to treat fibrolamellar hepatocellular carcinoma: A case report.

Fibrolamellar hepatocellular carcinoma (FL-HCC) is a rare primary liver tumor that typically presents at an advanced stage in early adolescents and adults with no underlying liver disease. Surgical resection is the first-line treatment, and patients who are not surgical candidates face limited treatment options with poor long-term outcomes. Herein we report the first documented, technically successful treatment of FL-HCC with extrahepatic spread using transarterial radioembolization (TARE) in a 16-year-old male patient with surgically unresectable disease. Subsequent imaging revealed tumor necrosis and a 20% reduction in size, and the patient survived 20 months post-treatment, a marked improvement relative to historical data in the literature. Further research should examine the potential role of yttrium-90 TARE in the treatment of FL-HCC patients with metastatic disease.

When doctors go to business school: career shoices of physician-MBAs.

There has been substantial growth in the number of physicians pursing Master of Business Administration (MBA) degrees over the past decade, but there is continuing debate over the utility of these programs and the career outcomes of their graduates. The authors analyzed the clinical and professional activities of a large cohort of physician-MBAs by gathering information on 206 physician graduates from the Harvard Business School MBA program who obtained their degrees between 1941 and 2014. Key outcome measures that were examined include medical specialty, current professional activity, and clinical practice. Chi square tests were used to assess the correlations in the data. Among the careers that were tracked (n = 195), there was significant heterogeneity in current primary employment. The most common sectors were clinical (27.7%), investment banking/finance (27.0%), hospital/provider administration (11.7%), biotech/device/pharmaceutical (10.9%), and entrepreneurship (9.5%). Overall, 84% of physician-MBAs entered residency; approximately half (49.3%) remained clinically active in some capacity and only one-fourth (27.7%) reported clinical medicine as their primary professional role. Among those who pursued residency training, the most common specialties were internal medicine (39.3%), emergency medicine (10.4%), orthopedic surgery (9.2%), and general surgery (8.6%). Physician-MBAs trained in internal medicine were significantly more likely to remain clinically active (63.8% vs 42.4%; P = .01). Clinical activity and primary employment in a clinical role decreased after degree conferment. After completing their education, a majority of physician-MBAs divert their primary professional focus away from clinical activity. These findings reveal new insights into the career outcomes of physician-MBAs.

PRC2 Is Required to Maintain Expression of the Maternal Gtl2-Rian-Mirg Locus by Preventing De Novo DNA Methylation in Mouse Embryonic Stem Cells.

Polycomb Repressive Complex 2 (PRC2) function and DNA methylation (DNAme) are typically correlated with gene repression. Here, we show that PRC2 is required to maintain expression of maternal microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) from the Gtl2-Rian-Mirg locus, which is essential for full pluripotency of iPSCs. In the absence of PRC2, the entire locus becomes transcriptionally repressed due to gain of DNAme at the intergenic differentially methylated regions (IG-DMRs). Furthermore, we demonstrate that the IG-DMR serves as an enhancer of the maternal Gtl2-Rian-Mirg locus. Further analysis reveals that PRC2 interacts physically with Dnmt3 methyltransferases and reduces recruitment to and subsequent DNAme at the IG-DMR, thereby allowing for proper expression of the maternal Gtl2-Rian-Mirg locus. Our observations are consistent with a mechanism through which PRC2 counteracts the action of Dnmt3 methyltransferases at an imprinted locus required for full pluripotency.