Pharmacodynamic separation of gemcitabine and erlotinib in locally advanced or metastatic pancreatic cancer: therapeutic and biomarker results.

PURPOSE: Erlotinib marginally improves survival when administered continuously with gemcitabine to patients with advanced pancreatic cancer; however, preclinical data suggest that there is antagonism between chemotherapy and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors when these are delivered concurrently. We tested a pharmacodynamic separation approach for erlotinib plus gemcitabine and interrogated EGFR signaling intermediates as potential surrogates for the efficacy of this strategy. METHODS: Patients with measurable, previously untreated locally advanced unresectable or metastatic pancreatic cancer were treated with gemcitabine 1000 mg/m(2) as an intravenous infusion over 30-min on days 1, 8, 15 and erlotinib 150 mg/day on days 2-5, 9-12, 16-26 of each 28-day cycle. The primary endpoint was progression-free survival (PFS); secondary endpoints included RECIST objective response rate (ORR) and safety. The study was terminated after thirty patients due to funding considerations. RESULTS: The median PFS was 2.07 months (95% CI; 1.87-5.50 months) and the ORR was 11%. No unexpected safety signals were seen: the most common grade 3 or higher adverse events were neutropenia (23%), lymphopenia (23%), and fatigue (13%). Patients with mutant plasma Kirsten rat sarcoma virus (KRAS) had significantly lower median PFS (1.8 vs. 4.6 months, p = 0.014) and overall survival (3.0 vs. 10.5 months, p = 0.003) than those without detected plasma KRAS mutations. CONCLUSIONS: Although pharmacodynamically separated erlotinib and gemcitabine were feasible and tolerable in patients with advanced pancreatic cancer, no signal for increased efficacy was seen in this molecularly unselected cohort. Detection of a KRAS mutation in circulating cell-free DNA was a strong predictor of survival.

Progressive left ventricular noncompaction and systolic dysfunction.

Left ventricular noncompaction is a condition characterized by prominent ventricular trabeculations, often accompanied by systolic dysfunction. The present case involves an adult with a small ventricular septal defect, initially exhibiting mild systolic dysfunction and slightly prominent left ventricular trabeculations progressing over 13 years to severe dilated cardiomyopathy and overt noncompaction. The present case strongly suggests a correlation between the extent of noncompaction and the degree of systolic dysfunction. The initial presence of a small ventricular septal defect and mild trabeculations highlights the genetic determinants of non-compaction and the importance of closely following patients with mild noncompaction due to the possibility of progression. More sensitive diagnostic criteria are needed to avoid overlooking mild cases, which may show prominent trabeculations without reaching a requisite ratio of compacted to noncompacted tissue.

Risk factors for posttraumatic vasospasm.

OBJECT: Posttraumatic vasospasm (PTV) is an underrecognized cause of ischemic damage after severe traumatic brain injury (TBI) that independently predicts poor outcome. There are, however, no guidelines for PTV screening and management, partly due to limited understanding of its pathogenesis and risk factors. METHODS: A database review of 46 consecutive cases of severe TBI in pediatric and adult patients was conducted to identify risk factors for the development of PTV. Univariate analysis was performed to identify potential risk factors for PTV, which were subsequently analyzed using a multivariate logistic regression model to calculate odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Fever on admission was an independent risk factor for development of PTV (OR 22.2, 95% CI 1.9-256.8), and patients with hypothermia on admission did not develop clinically significant vasospasm during their hospital stay. The presence of small parenchymal contusions was also an independent risk factor for PTV (OR 7.8, 95% CI 0.9-69.5), whereas the presence of subarachnoid hemorrhage or other patterns of intracranial injury were not. Other variables, such as age, sex, ethnicity, degree of TBI severity, or admission laboratory values, were not independent predictors for the development of clinically significant PTV. CONCLUSIONS: Independent risk factors for PTV include parenchymal contusions and fever. These results suggest that diffuse mechanical injury and activation of inflammatory pathways may be underlying mechanisms for the development of PTV, and that a subset of patients with these risk factors may be an appropriate population for aggressive screening. Further studies are needed to determine if treatments targeting fever and inflammation may be effective in reducing the incidence of vasospasm following severe TBI.