Multiplex Patient-Based Drug Response Assay in Pancreatic Ductal Adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDA) is an extremely lethal malignancy arising from the pancreas. The treatment of PDA is complicated by ineffective treatments and a lack of biomarkers predictive of treatment success. We have designed a patient-derived organoid (PDO) based high-throughput drug screening assay to model treatment response to a variety of conventional and investigational treatments for PDA. Consecutive patients undergoing endoscopic ultrasound-guided fine-needle biopsy for tissue diagnosis of PDA at Rush University Medical Center were offered to participate in the study. Biopsies were immediately processed to develop organoids. Fifteen PDOs were screened for sensitivity to 18 compounds, including conventional PDA chemotherapies and FDA-approved investigational targeted therapies in cancer using Cell-titer GLO 3D (Promega) cell viability assay. The area under the curve (AUC) was calculated and normalized to the maximum area under the curve to generate a normalized AUC between 0 and 1. Molecular profiling of PDOs was conducted using RNA-seq. Human PDA transcriptomic was extracted from The Cancer Genome Atlas (TCGA). The drug response curves were reproducible. We observed variation in response to conventional therapies overall as well as among individual patients. There were distinct transcriptome signatures associated with response to the conventional chemotherapeutics in PDA. The transcriptomic profile of overall resistance to conventional therapies in our study was associated with poor survival in PDA patients in TCGA. Our pathway analysis for targeted drugs revealed a number of predictors of response associated with the mechanism of action of the tested drug. The multiplex organoid-based drug assay could be used in preclinical to inform patient stratification and therapeutic selection in PDA. When combined with omics data, ex vivo response to treatment could help identify gene signatures associated with response to novel therapies.

Disrupted Circadian Rest-Activity Cycles in Inflammatory Bowel Disease Are Associated With Aggressive Disease Phenotype, Subclinical Inflammation, and Dysbiosis.

Patients with inflammatory bowel disease (IBD)-Crohn's disease (CD), and ulcerative colitis (UC), have poor sleep quality. Sleep and multiple immunologic and gastrointestinal processes in the body are orchestrated by the circadian clock, and we recently reported that a later category or chronotype of the circadian clock was associated with worse IBD specific outcomes. The goal of this study was to determine if circadian misalignment by rest-activity cycles is associated with markers of aggressive disease, subclinical inflammation, and dysbiosis in IBD. A total of 42 patients with inactive but biopsy-proven CD or UC and 10 healthy controls participated in this prospective cohort study. Subjects were defined as having an aggressive IBD disease history (steroid dependence, use of biologic or immunomodulator, and/or surgery) or non-aggressive history. All participants did two weeks of wrist actigraphy, followed by measurement of intestinal permeability and stool microbiota. Wrist actigraphy was used to calculate circadian markers of rest-activity- interdaily stability (IS), intradaily variability (IV), and relative amplitude (RA). Aggressive IBD history was associated with decrease rest-activity stability (IS) and increased fragmentation compared to non-aggressive IBD and health controls at 0.39 ±.15 vs. 0.51 ± 0.10 vs. 0.55 ± 0.09 (P < 0.05) and 0.83 ± 0.20 vs. 0.72 ± 0.14 (P < 0.05) but not HC at 0.72 ± 0.14 (P = 0.08); respectively. There was not a significant difference in RA by IBD disease history. Increased intestinal permeability and increased TNF-α levels correlated with an increased rest activity fragmentation (IV) at R = 0.35, P < 0.05 and R = 0.37, P < 0.05, respectively; and decreased rest-activity amplitude (RA) was associated with increased stool calprotectin at R = 0.40, P < 0.05. Analysis of intestinal microbiota showed a significant decrease in commensal butyrate producing taxa and increased pro-inflammatory bacteria with disrupted rest-activity cycles. In this study, different components of circadian misalignment by rest-activity cycles were associated with a more aggressive IBD disease history, increased intestinal permeability, stool calprotectin, increased pro-inflammatory cytokines, and dysbiosis. Wrist activity allows for an easy non-invasive assessment of circadian activity which may be an important biomarker of inflammation in IB.

Double Trouble: A Rare Case of Concurrent Biliary Adenofibroma and Hepatobiliary Mucinous Cystic Neoplasm.

Biliary adenofibroma and hepatobiliary mucinous cystic neoplasm are exceedingly rare tumors. To our knowledge, no case of co-existent biliary adenofibroma and mucinous cystic neoplasm has been previously reported. We present a patient who was diagnosed with both tumors concurrently. Both can present with abdominal pain, although some are diagnosed incidentally in asymptomatic patients. Imaging and tumor markers can be suggestive, but histologic examination is needed for definitive diagnosis. Both have a propensity for malignant transformation, thus complete surgical resection is the treatment of choice. Although rare, awareness of these tumors leads to earlier diagnosis and treatment.

Update 2014: advances to optimize 6-mercaptopurine and azathioprine to reduce toxicity and improve efficacy in the management of IBD.

BACKGROUND: The thiopurine drugs, 6-mercaptopurine (6-MP) and azathioprine (AZA), remain as a mainstay therapy in inflammatory bowel disease (IBD). Differences in metabolism of these drugs lead to individual variation in thiopurine metabolite levels that can determine its therapeutic efficacy and development of adverse reactions. In this update, we will review thiopurine metabolic pathway along with the up-to-date approaches in administering thiopurine medications based on the current literature. METHODS: A search of the PubMed database by 2 independent reviewers identifying 98 articles evaluating thiopurine metabolism and IBD management. RESULTS: Monitoring thiopurine metabolites can assist physicians in optimizing 6-MP and AZA therapy in treating patients with IBD. Of the dosing strategies reviewed, we found evidence for monitoring thiopurine metabolite level, use of allopurinol with thiopurine, use of mesalamine with thiopurine, combination therapy with thiopurine and anti-tumor necrosis factor agents, and split dosing of AZA or 6-MP to optimize thiopurine therapy and minimize adverse effects in IBD. CONCLUSIONS: Based on the currently available literature, various dosing strategies to improve therapeutic response and reduce adverse reactions can be considered, including use of allopurinol with thiopurine, use of mesalamine with thiopurine, combination therapy with thiopurine and anti-tumor necrosis factor agents, and split dosing of thiopurine.