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• Lymphangitic carcinomatosis (LC) correlates with a poor prognosis in many cancers. • LC is a common pattern of failure after pleurectomy/decortication for mesothelioma. • The emergence of the LC pattern was associated with a worse overall survival. The lymphangitic carcinomatosis (LC) pattern of metastatic malignancy is associated with a poor prognosis but is currently not well defined in malignant pleural mesothelioma (MPM). Here, we report the incidence and prognostic significance of the radiographic development of LC in MPM following extended pleurectomy/decortication (EPD). Consecutive patients with biopsy-proven MPM undergoing EPD with intraoperative photodynamic therapy (PDT) at our institution from 2008 to 2014 were included in this retrospective study. Patients without available post-surgical clinical or imaging data for direct review were excluded. CT images were reviewed by an experienced, board-certified thoracic radiologist and confirmed by consensus review. Overall survival (OS) and progression-free survival (PFS) were calculated by Kaplan Meier methodology. Hazard ratios were compared with a cox proportional hazard model. 44 patients underwent EPD with PDT during the study period and had available clinical and imaging data. During the follow-up period (median 34 months), 17 patients (39%) developed LC at a median of 10 months after surgery (IQR 5–21 months). 16 of the 17 patients who developed LC (94%) died during the follow-up period, compared to 17 of the 27 who did not develop LC (63%). OS for the LC versus non-LC group was 53% versus 93% at 1 year and 18% versus 67% at 3 years. LC was significantly associated with a lower OS (HR 4.07; 95% confidence interval 1.44–11.48; p = 0.008). PFS for the LC group versus non-LC group was 8 months (IQR 5–9 months) compared to 17 months (IQR 11–24 months) (p < 0.001). LC is a common form of failure in MPM following EPD and is associated with a poor prognosis. Thus, further studies are warranted to determine if any evidence of preoperative LC should be an absolute contraindication to EPD and may warrant an EPP or no surgery at all. [ABSTRACT FROM AUTHOR]

Background: Cross-sectional imaging of malignant pleural mesothelioma (MPM) can underestimate the presence of local tumor invasion. Since accurate staging is vital optimal choice of therapy, techniques that optimize pleural imaging are needed. Here we estimate the optimal timing of MPM enhancement on magnetic resonance imaging (MRI)., Methods: All MPM patients with intravenous (IV) contrast enhanced staging MRI between 2000-2016 at our institution were retrospectively selected for image analysis. Patients with incomplete imaging protocol and maximum pleural tumor thickness <1 cm were excluded. Quantitative measurements of tumor signal intensity were obtained on pre-contrast and post-contrast phases where MRI acquisition parameters were fixed. Using best-fit model curves, predicted maximum time points of enhancement were determined using a simulation of predicted values. Additionally, a qualitative assessment of tumor conspicuity was performed at all IV contrast time delays imaged. A statistical analysis assessed for correlation between qualitative lesion conspicuity and quantitative tumor enhancement., Results: Of the 42 MPM patients who had undergone staging MRI during the study period, 12 patients met the study criteria. Peak tumor enhancement was between 150 and 300 sec following IV contrast administration. Within this time window, 80% of patients are projected to have reached >80%, >85%, and >90% peak tumor enhancement. There was a statistically significant correlation between increasing tumor enhancement and subjective lesion conspicuity., Conclusions: Optimal MPM enhancement on MRI likely occurs at a time delay between 2.5-5 min following IV contrast administration. Further study of delayed phase enhancement of MPM with dynamic contrast enhanced MRI is warranted., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

Inhibition of thymidylate synthase (TS) results in a transient "flare" in DNA thymidine salvage pathway activity measurable with FLT ([18F]thymidine)-positron emission tomography (PET). Here we characterize this imaging strategy for potential clinical translation in non-small cell lung cancer (NSCLC). Since pemetrexed acts by inhibiting TS, we defined the kinetics of increases in thymidine salvage pathway mediated by TS inhibition following treatment with pemetrexed in vitro. Next, using a mouse model of NSCLC, we validated the kinetics of the pemetrexed-mediated "flare" in thymidine salvage pathway activity in vivo using FLT-PET imaging. Finally, we translated our findings into a proof-of-principle clinical trial of FLT-PET in a human NSCLC patient. In NSCLC cells in vitro, we identified a burst in pemetrexed-mediated thymidine salvage pathway activity, assessed by 3H-thymidine assays, thymidine kinase 1 (TK1) expression, and equilibrative nucleoside transporter 1 (ENT1) mobilization to the cell membrane, that peaked at 2hrs. This 2hr time-point was also optimal for FLT-PET imaging of pemetrexed-mediated TS inhibition in murine xenograft tumors and was demonstrated to be feasible in a NSCLC patient. FLT-PET imaging of pemetrexed-induced TS inhibition is optimal at 2hrs from therapy start; this timing is feasible in human clinical trials.