e15672 Background: Rare tumors, such as cholangiocarcinoma (CC), have no established treatment protocols, forcing clinicians to select therapies based on educated guesses or small case series. Genomic tumor analyses fail to identify options for most patients. Here, we show the feasibility of using a high-throughput functional assay to test targeted drug libraries on individual patient-derived tumor organoids from CC to yield experimentally-validated therapeutic options. Methods: Three consecutive patients with CC who were undergoing a standard of care biopsy or resection were enrolled in an IRB-approved study. Patient characteristics, demographics, tumor pathology, including Next Generation Sequencing (NGS) data and organoid-derived drug recommendations are shown in the Table. Specimen (~ 200 mg of tumor) was shipped on ice overnight to SEngine Precision Medicine for tumor-derived organoid culture and sensitivity analysis. Organoids were evaluated using a multi-dose response to each drug in a library of 120 FDA-approved and investigational drugs and compared those responses to all prior patients. This established both functional sensitivity and the uniqueness of each patient’s response. Results: We tested operational logistics, tumor growth rates, and chemosensitivity reporting timelines. This has allowed us to: 1) operationalize the expansion process, 2) quantify turn-around time, and 3) identify any technical or logistic barriers. All specimens resulted in adequate growth for sensitivity characterization. None of the NGS studies resulted in recommendations for sensitivity to targeted chemotherapy. Conversely, tumor organoid assays rapidly identified selective, personalized drugs. Conclusions: We have shown the feasibility of this approach in CC. Our preliminary results will inform the design of a future prospective clinical trial to establish and validate this method to select personalized cancer treatments for rare malignancies.[Table: see text]

Hepatic encephalopathy (HE) is a common complication of advanced liver disease causing brain dysfunction. This is likely due to the accumulation of unfiltered toxins within the bloodstream. A known risk factor for developing or worsening HE is the placement of a transjugular intrahepatic portosystemic shunt (TIPS), which connects the pre-hepatic and post-hepatic circulation allowing some blood to bypass the dysfunctional liver and decreases portal hypertension. To better understand the pathophysiology of post-TIPS HE, we conducted a multi-center prospective cohort study employing metabolomic analyses on hepatic vein and peripheral vein blood samples from participants with cirrhosis undergoing elective TIPS placement, measuring chemical modifications and changes in concentrations of metabolites resulting from TIPS placement. In doing so, we identified numerous alterations in metabolites, including bile acids, glycerophosphocholines, and bilirubins possibly implicated in the development and severity of HE.

Rapid improvements in medical technology, big data analysis, and molecular medicine come with promises of revolutionizing medical care. They span the spectrum from diagnostics to genome-based drug selection to multi-biomarker analysis to deciphering large amounts of data. Below, recent developments in personalized and precision medicine are reviewed, focusing specifically on the liver, ranging from fatty liver disease to liver cancer treatment and liver transplantation. Furthermore, current technologies and their advantages and limitations are discussed, in addition to ways in which these disadvantages can be overcome, using phenotypic personalized medicine.

Background: Inter- and intra-individual variability in tacrolimus dose requirements mandates empirical clinician-titrated dosing that frequently results in deviation from a narrow target range. Improved methods to individually dose tacrolimus are needed. Our objective was to determine whether a quantitative, dynamically-customized, phenotypic-outcome-guided dosing method termed Phenotypic Personalized Medicine (PPM) would improve target drug trough maintenance. Methods: In a single-center, randomized, pragmatic clinical trial (NCT03527238), 62 adults were screened, enrolled, and randomized prior to liver transplantation 1:1 to standard-of-care (SOC) clinician-determined or PPM-guided dosing of tacrolimus. The primary outcome measure was percent days with large (>2 ng/mL) deviation from target range from transplant to discharge. Secondary outcomes included percent days outside-of-target-range and mean area-under-the-curve (AUC) outside-of-target-range per day. Safety measures included rejection, graft failure, death, infection, nephrotoxicity, or neurotoxicity. Results: 56 (29 SOC, 27 PPM) patients completed the study. The primary outcome measure was found to be significantly different between the two groups. Patients in the SOC group had a mean of 38.4% of post-transplant days with large deviations from target range; the PPM group had 24.3% of post-transplant days with large deviations; (difference -14.1%, 95% CI: -26.7 to -1.5 %, P=0.029). No significant differences were found in the secondary outcomes. In post-hoc analysis, the SOC group had a 50% longer median length-of-stay than the PPM group [15 days (Q1-Q3: 11-20) versus 10 days (Q1-Q3: 8.5-12); difference 5 days, 95% CI: 2-8 days, P=0.0026]. Conclusions: PPM guided tacrolimus dosing leads to better drug level maintenance than SOC. The PPM approach leads to actionable dosing recommendations on a day-to-day basis.

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