Does addition of a diagnostic contrast-enhanced CT to a contemporaneous PET/CT provide incremental value in patients for restaging of colorectal carcinoma?

Abstract Background Both constrast-enhanced computed tomography (ceCT) and 18F-Fluorodeoxyglucose positron emission tomography (PET) are widely used for evaluation of colorectal cancer. Not infrequently patients undergo both tests, increasing cost and radiation burden. Whether this combination provides useful incremental diagnostic information remains unclear. Our purpose was to determine whether the addition of ceCT to PET/CT results in an appropriate change in the N or M stage in patients with colorectal cancer. Methods This was a single centre, retrospective study in a tertiary referral hospital. Over 9 months, 74 consecutive patients with colorectal carcinoma were referred for PET with a recent ceCT scan and adequate follow-up were analysed. The N and M stage of each modality was compared. Management was determined according to institutional guidelines with incremental impact of ceCT results on management categorised as appropriate, inappropriate or unchanged, based on pathological results, clinical or imaging follow-up of discrepant findings. Results Of 74 patients, PET/CT and ceCT N and M stages were concordant in 56 patients (76%) but PET/CT and ceCT identified additional abnormalities in 9 cases each respectively. Of the 18 discordant cases, accepting the ceCT result would have appropriately changed management in only 2 patients and inappropriately in 1 with most management plans unchanged. When comparing PET/CT and ceCT, kappa agreement (95% confidence interval) for N and M stage was 0.58 (0.20–0.95) and 0.60(0.41–0.79) respectively reflecting moderate agreement. Conclusions Whole-body ceCT probably has limited management impact in colorectal cancer patients who are also undergoing PET/CT and therefore may possibly be omitted from routine use. Targeted regional MRI or ceCT should, however, be considered based on clinical suspicion or when high-resolution anatomical information is required for treatment planning

Mitogen-activated protein kinase pathway inhibition for redifferentiation of radioiodine refractory differentiated thyroid cancer: an evolving protocol

Background: Some patients with metastatic differentiated thyroid cancer (DTC) lack iodine avidity and are therefore unsuitable for radioactive iodine (RAI) therapy. Limited experience suggests that single-agent selective mitogen-activated protein kinase (MAPK) pathway inhibitors can restore expression of the sodium-iodide symporter rendering RAI refractory (RAIR) DTC patients amenable to RAI therapy. The aim of this study was to assess the feasibility of mutation-guided MAPK-pathway blockade combined with thyroid hormone withdrawal (THW) for redifferentiation. Methods: This is a retrospective review of metastatic RAIR DTC and driver mutation in MAPK pathway, treated on a redifferentiation protocol. All patients had metastatic disease that had never been RAI-avid and/or imaging and biochemical progression despite treatment with RAI within the past 12 months. Patients with tumors harboring an NRAS mutation were treated with an MEK inhibitor (trametinib), and tumors with a BRAF(V600E) mutation with combined BRAF and MEK inhibition (dabrafenib and trametinib; or vemurafenib and cobimetinib) for four weeks. Thyrotropin stimulation was performed by THW for four weeks. Restoration of RAI uptake was determined by I-124 positron emission tomography/computed tomography imaging. The response was assessed at least three months post-RAI. Results: From 2015 to 2017, six patients (age 45-70, four females) received redifferentiation therapy. Three patients had an NRAS mutation; two with follicular thyroid carcinoma (FTC) and one with a poorly differentiated thyroid carcinoma (PDTC); and three patients had a BRAF(V600E) mutation and papillary thyroid carcinoma (PTC). One NRAS and all BRAF(V600E) mutation cases demonstrated restoration of RAI uptake and proceeded to RAI therapy with a median follow-up of 16.6 months (range 13.5-42.3 months). The patient with an NRAS mutation and two of three patients with a BRAF(V600E) demonstrated partial imaging response beyond a three-month follow-up. Grade 3 adverse events (acneiform rash) were observed in two patients with NRAS mutations. Conclusions: Mutation-guided MAPK pathway inhibition with MEK inhibitor or a combination of BRAF inhibitor and MEK inhibitor under concurrent THW is a feasible and a promising strategy to redifferentiate RAIR DTC, thereby rendering them suitable for RAI therapy with satisfactory retention following treatment

Cells exposed to antifolates show increased cellular levels of proteins fused to dihydrofolate reductase: A method to modulate gene expression

Human cells exposed to antifolates show a rapid increase in the levels of the enzyme dihydrofolate reductase (DHFR). We hypothesized that this adaptive response mechanism can be used to elevate cellular levels of proteins fused to DHFR. In this study, mouse cells transfected to express a green fluorescent protein-DHFR fusion protein and subsequently exposed to the antifolate trimetrexate (TMTX) showed a specific and time-dependent increase in cellular levels of the fusion protein. Next, human HCT-8 and HCT-116 colon cancer cells retrovirally transduced to express a DHFR-herpes simplex virus 1 thymidine kinase (HSV1 TK) fusion protein and treated with the DHFR inhibitor TMTX exhibited increased levels of the DHFR-HSV1 TK fusion protein and an increase in ganciclovir sensitivity by 250-fold. The level of fusion protein in antifolate-treated human tumor cells was increased in response to a 24-h exposure of methotrexate, trimetrexate, as well as dihydrofolate. This effect depended on the antifolate concentration and was independent of the fusion-protein mRNA levels, consistent with this increase occurring at a translational level. In a xenograft model, nude rats bearing DHFR-HSV1 TK-transduced HCT-8 tumors and treated with TMTX showed, after 24 h, a 2- to 4-fold increase of fusion-protein levels in tumor tissue from treated animals compared with controls, as determined by Western blotting. The fusion-protein increase was imaged with positron-emission tomography, where a substantially enhanced signal of the transduced tumor was detected in animals after antifolate administration. Drug-mediated elevation of cellular DHFR-fused proteins is a very useful method to modulate gene expression in vivo for imaging as well as therapeutic purposes