Molecular Alterations Associated with DNA Repair in Pancreatic Adenocarcinoma Are Associated with Sites of Recurrence.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest malignancies with a rising incidence. Mutational analysis of PDAC has provided valuable information but has not yet dramatically changed the therapeutic landscape due to the number of variations detected in any one individual. The pattern of molecular alterations-gene mutations, variations in copy number, and changes in gene expression-has been described in the literature. The purpose of this study is to further investigate the molecular alterations in recurrent or metastatic PDAC based on the site of disease. METHODS: Molecular alterations in patients with recurrent or metastatic PDAC from 2007 to 2015 were analyzed. The most common molecular alterations found in PDAC tumors from the pancreas were compared to metastatic PDAC specimens from the liver, lung, peritoneum, and other locations. Means were compared with a two-tailed Student's t test or ANOVA as appropriate. Rates of molecular alterations among the different groups were compared with Pearson's χ2. RESULTS: Two thousand five hundred fifty-two patients with PDAC were identified in a retrospective database, and the 15 most common molecular alterations were utilized for analysis. The most common alterations among all patients were mutations in KRAS and PTEN (59 and 62%, respectively), with differences in prevalence by site of metastasis (p = 0.042 and p = 0.037, respectively). KRAS mutations were more commonly found in metastasis in the lung (72%) than in other sites (59%, p = 0.042). Low expression of ERCC1 was found in 49% of lung metastases from PDAC but only 15% in PDAC in the pancreas (p < 0.001). Five of the 8 molecular alterations significantly associated with site of metastatic disease were involved in DNA maintenance, repair, replication, or transcription (each p < 0.001). CONCLUSIONS: Aberrant expression or mutation in genes involved in DNA maintenance is found in association with specific sites of metastatic PDAC. Personalizing therapy for metastatic PDAC based on site of disease and their associated molecular alterations warrants further investigation.

Propofol Infusion Syndrome: Efficacy of a Prospective Screening Protocol.

Propofol infusion syndrome (PIS) is a potentially lethal complication of propofol marked by rhabdomyolysis, metabolic acidosis, and cardiac arrhythmias or collapse. The objective of this study was to determine the effectiveness of a prospective screening protocol to prevent PIS. All trauma patients admitted who received propofol as a continuous infusion were prospectively screened from November 1, 2013 to December 31, 2015. Variables studied included demographics, injury severity, laboratory values, infusion rates, and mortality. Serum creatine phosphokinase (CPK) and lactate were drawn daily. Propofol was stopped for a positive screen defined as an increase in CPK to greater than 5000 IU/L or lactate greater than 4 mmol/L. Positive and negative cohorts were compared. Two hundred and twenty-five patients met the inclusion criteria and 12 patients (5.3%) had propofol stopped because of elevated CPK. No differences were identified in demographics, transfusions, injury severity, hospital length of stay, or propofol dose. The positive screened group had longer intensive care unit length of stay (20 vs 13 days; P = 0.002) and increased vent days (14.5 vs 10 days; P = 0.008). Max serum osmolality (334 vs 305 mosm/kg; P = 0.049) and max serum CPK (6782 vs 1058 IU/L; P < 0.0001) were higher in the positive cohort. No cases of PIS occurred, and mortality (16.7 vs 15.5%; P = 0.999) was not different between the cohorts. The screening protocol was effective in eliminating PIS. Serial CPK evaluations provided an effective screening tool and serum lactate can be dropped from screening.