Patient-derived Organoid Pharmacotyping is a Clinically Tractable Strategy for Precision Medicine in Pancreatic Cancer

Objective: PDAC patients who undergo surgical resection and receive effective chemotherapy have the best chance of long-term survival. Unfortunately, we lack predictive biomarkers to guide optimal systemic treatment. Ex-vivo generation of PDO for pharmacotyping may serve as predictive biomarkers in PDAC. The goal of the current study was to demonstrate the clinical feasibility of a PDO-guided precision medicine framework of care. Methods: PDO cultures were established from surgical specimens and endoscopic biopsies, expanded in Matrigel, and used for high-throughput drug testing (pharmacotyping). Efficacy of standard-of-care chemotherapeutics was assessed by measuring cell viability after drug exposure. Results: A framework for rapid pharmacotyping of PDOs was established across a multi-institutional consortium of academic medical centers. Specimens obtained remotely and shipped to a central biorepository maintain viability and allowed generation of PDOs with 77% success. Early cultures maintain the clonal heterogeneity seen in PDAC with similar phenotypes (cystic-solid). Late cultures exhibit a dominant clone with a pharmacotyping profile similar to early passages. The biomass required for accurate pharmacotyping can be minimized by leveraging a high-throughput technology. Twenty-nine cultures were pharmacotyped to derive a population distribution of chemotherapeutic sensitivity at our center. Pharmacotyping rapidly-expanded PDOs was completed in a median of 48 (range 18-102) days. Conclusions: Rapid development of PDOs from patients undergoing surgery for PDAC is eminently feasible within the perioperative recovery period, enabling the potential for pharmacotyping to guide postoperative adjuvant chemotherapeutic selection. Studies validating PDOs as a promising predictive biomarker are ongoing.Peer reviewe

Characteristics of US hospitals using extraordinary collections actions against patients for unpaid medical bills: a cross-sectional study

Objective This study aims to characterise and evaluate the largest 100 hospitals in the USA that have adopted aggressive collection tactics to pursue patients with unpaid medical bills, such as lawsuits, wage garnishments and liens.Design Cross-sectional study.Setting We examined state and county court record systems to measure the magnitude and prevalence of these practices at the largest 100 hospitals in the UA between 1 January 2018 and 31 July 2020.Main outcomes measures The main outcome of this study was the number of lawsuits, wage garnishments and liens. A secondary outcome was the characterisation of a hospital’s safety, charitability, size and financial practices.Results Between 1 January 2018 and 31 July 2020, 26 hospitals filed 38 965 court actions (lawsuits, wage garnishments and liens) against patients for unpaid medical debt. For 16 of 26 hospitals, the dollar amount pursued in the court claim was available for 100% of cases, totalling US$71.8 million. The average aggregate amount sought by hospital lawsuits during the study period was US$4.5 million. Three hospitals filed US$56.2 million in amounts pursued in court, or 78.3% of the total amount pursued by all hospitals in the sample. In the remaining 74 hospitals, the study team did not identify extraordinary collection actions through the court system.Conclusions Standardised medical debt collections best practices and metrics of medical debt collections quality are needed to increase public accountability for hospitals, particularly non-profit hospitals. There is a need to re-evaluate Internal Revenue Service rules pertaining to non-profit hospitals’ tax-exempt status to ensure tax-exempt hospitals provide community benefits commensurate with the value of tax exemption

Circulating tumor DNA as a clinical test in resected pancreatic cancer

Purpose: In research settings, circulating tumor DNA (ctDNA) shows promise as a tumor-specific biomarker for pancreatic ductal adenocarcinoma (PDAC). This study aims to perform analytical and clinical validation of a KRAS ctDNA assay in a Clinical Laboratory Improvement Amendments (CLIA) and College of American Pathology–certified clinical laboratory. Experimental Design: Digital-droplet PCR was used to detect the major PDAC-associated somatic KRAS mutations (G12D, G12V, G12R, and Q61H) in liquid biopsies. For clinical validation, 290 preoperative and longitudinal postoperative plasma samples were collected from 59 patients with PDAC. The utility of ctDNA status to predict PDAC recurrence during follow-up was assessed. Results: ctDNA was detected preoperatively in 29 (49%) patients and was an independent predictor of decreased recurrence-free survival (RFS) and overall survival (OS). Patients who had neoadjuvant chemotherapy were less likely to have preoperative ctDNA than were chemo-na€ve patients (21% vs. 69%; P < 0.001). ctDNA levels dropped significantly after tumor resection. Persistence of ctDNA in the immediate postoperative period was associated with a high rate of recurrence and poor median RFS (5 months). ctDNA detected during follow-up predicted clinical recurrence [sensitivity 90% (95% confidence interval (CI), 74%–98%), specificity 88% (95% CI, 62%–98%)] with a median lead time of 84 days (interquartile range, 25–146). Detection of ctDNA during postpancreatectomy follow-up was associated with a median OS of 17 months, while median OS was not yet reached at 30 months for patients without ctDNA (P ¼ 0.011). Conclusions: Measurement of KRAS ctDNA in a CLIA laboratory setting can be used to predict recurrence and survival in patients with PDAC